In 1507–1508 Giorgione was commissioned by the state to create frescoes on the re-erected Fondaco dei Tedeschi. Titian and Morto da Feltre worked along with him, and some fragments of paintings remain, probably by Giorgione. Some of their work is known, in part, through the engravings of Fontana. After Giorgione's early death in 1510, Titian continued to paint Giorgionesque subjects for some time, though his style developed its own features, including bold and expressive brushwork.

A Man with a Quilted Sleeve is an early portrait, painted around 1509 and described by Giorgio Vasari in 1568. Scholars long believed it depicted Ludovico Ariosto, but now think it is of Gerolamo Barbarigo. Rembrandt borrowed the composition for his self-portraits.

Another famous painting is Bacchus and Ariadne, depicting Theseus, whose ship is shown in the distance and who has just left Ariadne at Naxos, when Bacchus arrives, jumping from his chariot, drawn by two cheetahs, and falling immediately in love with Ariadne. Bacchus raised her to heaven. Her constellation is shown in the sky. The painting belongs to a series commissioned from Bellini, Titian, and Dosso Dossi, for the Camerino d'Alabastro (Alabaster Room) in the Ducal Palace, Ferrara, by Alfonso I d'Este, Duke of Ferrara, who in 1510 even tried to commission Michelangelo and Raphael.

Titian's talent in fresco is shown in those he painted in 1511 at Padua in the Carmelite church and in the Scuola del Santo, some of which have been preserved, among them the Meeting at the Golden Gate, and three scenes (Miracoli di sant'Antonio) from the life of St. Anthony of Padua, The Miracle of the Jealous Husband, which depicts the Murder of a Young Woman by Her Husband, A Child Testifying to Its Mother's Innocence, and The Saint Healing the Young Man with a Broken Limb.

In 1512 Titian returned to Venice from Padua; in 1513 he obtained a broker's patent, termed La Sanseria or Senseria (a privilege much coveted by rising or risen artists), in the Fondaco dei Tedeschi. He became superintendent of the government works, especially charged with completing the paintings left unfinished by Giovanni Bellini in the hall of the great council in the ducal palace. He set up an atelier on the Grand Canal at S. Samuele, the precise site being now unknown. It was not until 1516, after the death of Giovanni Bellini, that he came into actual enjoyment of his patent. At the same time he entered an exclusive arrangement for painting. The patent yielded him a good annuity of 20 crowns and exempted him from certain taxes. In return he was bound to paint likenesses of the successive Doges of his time at the fixed price of eight crowns each. The actual number he painted was five.

During this period (1516–1530), which may be called the period of his mastery and maturity, the Artist moved on from his early Giorgionesque style, undertook larger, more complex subjects, and for the first time attempted a monumental style. Giorgione died in 1510 and Giovanni Bellini in 1516, leaving Titian unrivaled in the Venetian School. For sixty years he was the undisputed master of Venetian painting. In 1516, he completed his famous masterpiece, the Assumption of the Virgin, for the high altar of the Basilica di Santa Maria Gloriosa dei Frari, where it is still in situ. This extraordinary piece of colourism, executed on a grand scale rarely before seen in Italy, created a sensation. The Signoria took note and observed that Titian was neglecting his work in the hall of the great council, but in 1516 he succeeded his master Giovanni Bellini in receiving a pension from the Senate.

Titian never attempted engraving, but he was very conscious of the importance of printmaking as a means to expand his reputation. In the period 1517–1520 he designed a number of woodcuts, including an enormous and impressive one of The Crossing of the Red Sea, and collaborated with Domenico Campagnola and others, who produced additional prints based on his paintings and drawings. Much later he provided drawings based on his paintings to Cornelis Cort from the Netherlands who engraved them. Martino Rota followed Cort from about 1558 to 1568.

The Artist simultaneously continued a series of small Madonnas, which he placed amid beautiful landscapes, in the manner of genre pictures or poetic pastorals. The Virgin with the Rabbit, in The Louvre, is the finished type of these pictures. Another work of the same period, also in the Louvre, is the Entombment. This was also the period of the three large and famous mythological scenes for the camerino of Alfonso d'Este in Ferrara, The Bacchanal of the Andrians and the Worship of Venus in the Museo del Prado, and the Bacchus and Ariadne (1520–23) in London, "perhaps the most brilliant productions of the neo-pagan culture or "Alexandrianism" of the Renaissance, many times imitated but never surpassed even by Rubens himself."

Titian was then at the height of his fame, and towards 1521, following the production of a figure of St. Sebastian for the papal legate in Brescia (of which there are numerous replicas), purchasers pressed for his work.

Titian's wife, Cecilia, was a barber's daughter from his hometown village of Cadore. As a young woman she had been his housekeeper and mistress for some five years. Cecilia had already borne Titian two fine sons, Pomponio and Orazio, when in 1525 she fell seriously ill. Titian, wishing to legitimize the children, married her. Cecilia recovered, the marriage was a happy one, and they had another daughter who died in infancy. In August 1530 Cecilia died. Titian remarried, but little information is known about his second wife; she was possibly the mother of his daughter Lavinia. Titian had a fourth child, Emilia, the result of an affair, possibly with a housekeeper. His favorite child was Orazio, who became his assistant.

In August 1530 Titian moved his two boys and infant daughter to a new home and convinced his sister Orsa to come from Cadore and take charge of the household. The mansion, difficult to find now, is in the Biri Grande, then a fashionable suburb, at the extreme end of Venice, on the sea, with beautiful gardens and a view towards Murano. In about 1526 he had become acquainted, and soon close friends, with Pietro Aretino, the influential and audacious figure who features so strangely in the chronicles of the time. Titian sent a portrait of him to Gonzaga, duke of Mantua.

These qualities show in the Portrait of Pope Paul III of Naples, or the Sketch of the same Pope Paul III and his Grandsons, the Portrait of Pietro Aretino of the Pitti Palace, the Portrait of Isabella of Portugal (Madrid), and the series of Emperor Charles V of the same museum, the Charles V with a Greyhound (1533), and especially the Equestrian Portrait of Charles V (1548), an Equestrian picture in a symphony of purples. This state portrait of Charles V (1548) at the Battle of Mühlberg established a new genre, that of the grand Equestrian portrait. The composition is steeped both in the Roman tradition of Equestrian sculpture and in the medieval representations of an ideal Christian knight, but the weary figure and face have a subtlety few such representations attempt. In 1532, after painting a portrait of the Emperor Charles V in Bologna, he was made a Count Palatine and knight of the Golden Spur. His children were also made nobles of the Empire, which for a Painter was an exceptional honor.

As a matter of professional and worldly success his position from about this time is regarded as equal only to that of Raphael, Michelangelo and, at a later date, Rubens. In 1540 he received a pension from d'Avalos, marquis del Vasto, and an annuity of 200 crowns (which was afterwards doubled) from Charles V from the treasury of Milan. Another source of profit, for he was always aware of money, was a contract obtained in 1542 for supplying grain to Cadore, where he visited almost every year and where he was both generous and influential.

Marco Vecellio, called Marco di Tiziano, Titian's nephew, born in 1545, was constantly with the master in his old age, and learned his methods of work. He has left some able productions in the ducal palace, the Meeting of Charles V. and Clement VII. in 1529; in S. Giacomo di Rialto, an Annunciation; in SS. Giovani e Paolo, Christ Fulminant. A son of Marco, named Tiziano (or Tizianello), painted early in the 17th century.

He visited Rome in 1546 and obtained the freedom of the city—his immediate predecessor in that honor having been Michelangelo in 1537. He could at the same time have succeeded the Painter Sebastiano del Piombo in his lucrative office as holder of the piombo or Papal seal, and he was prepared to take Holy Orders for the purpose; but the project lapsed through his being summoned away from Venice in 1547 to paint Charles V and others in Augsburg. He was there again in 1550, and executed the portrait of Philip II, which was sent to England and was useful in Philip's suit for the hand of Queen Mary.

During the last twenty-six years of his life (1550–1576), Titian worked mainly for Philip II and as a portrait-painter. He became more self-critical, an insatiable perfectionist, keeping some pictures in his studio for ten years—returning to them and retouching them, constantly adding new expressions at once more refined, concise, and subtle. He also finished many copies that his pupils made of his earlier works. This caused problems of attribution and priority among versions of his works—which were also widely copied and faked outside his studio during his lifetime and afterwards.

Titian had engaged his daughter Lavinia, the beautiful girl whom he loved deeply and painted various times, to Cornelio Sarcinelli of Serravalle. She had succeeded her aunt Orsa, then deceased, as the manager of the household, which, with the lordly income that Titian made by this time, placed her on a corresponding footing. The marriage took place in 1554. She died in childbirth in 1560.

Titian was at the Council of Trent towards 1555, of which there is a finished Sketch in the Louvre. His friend Aretino died suddenly in 1556, and another close intimate, the Sculptor and Architect Jacopo Sansovino, in 1570. In September 1565 Titian went to Cadore and designed the decorations for the church at Pieve, partly executed by his pupils. One of these is a Transfiguration, another an Annunciation (now in S. Salvatore, Venice), inscribed Titianus fecit, by way of protest (it is said) against the disparagement of some persons who caviled at the veteran's failing handicraft.

Around 1560, Titian painted the oil on canvas, Madonna and Child with Saints Luke and Catherine of Alexandria, a derivative on the motif of Madonna and Child. It is suggested that members of Titian's Venice workshop probably painted the curtain and Luke, because of the lower quality of those parts.

While the plague raged in Venice, Titian died of a fever on 27 August 1576. Depending on his unknown birthdate (see above), he was somewhere from his late eighties or even close to 100. Titian was interred in the Frari (Basilica di Santa Maria Gloriosa dei Frari), as at first intended, and his Pietà was finished by Palma il Giovane. He lies near his own famous painting, the Madonna di Ca' Pesaro. No memorial marked his grave. Much later the Austrian rulers of Venice commissioned Antonio Canova to sculpt the large monument still in the church.

From a different branch of the family came Fabrizio di Ettore, a Painter who died in 1580. His brother Cesare, who also left some pictures, is well known by his book of engraved costumes, Abiti antichi e moderni. Tommaso Vecelli, also a Painter, died in 1620. There was another relative, Girolamo Dante, who, being a scholar and assistant of Titian, was called Girolamo di Tiziano. Various pictures of his were touched up by the master, and are difficult to distinguish from originals.

Contemporary estimates attribute around 400 works to Titian, of which about 300 survive. Two of Titian's works in private hands were put up for sale in 2008. One of these, Diana and Actaeon, was purchased by London's National Gallery and the National Galleries of Scotland on 2 February 2009 for ₤50 million ($71 million). The galleries had until 31 December 2008 to make the purchase before the work would be offered to private Collectors, but the deadline was extended. The other painting, Diana and Callisto, was for sale for the same amount until 2012 before it was offered to private Collectors. The sale created controversy with politicians who argued that the money could have been spent more wisely during a deepening recession. The Scottish Government offered ₤12.5 million and ₤10 million came from the National Heritage Memorial Fund. The rest of the money came from the National Gallery and from private donations.

At this time also, during his visit to Rome, the Artist began a series of reclining Venuses: The Venus of Urbino of the Uffizi, Venus and Love at the same museum, Venus—and the Organ-Player, Madrid, which shows the influence of contact with ancient sculpture. Giorgione had already dealt with the subject in his Dresden picture, finished by Titian, but here a purple drapery substituted for a landscape background changed, by its harmonious colouring, the whole meaning of the scene.