Tonegawa was born in Nagoya, Japan and attended Hibiya High School in Tokyo. While a student at Kyoto University, Tonegawa became fascinated with operon theory after reading papers by François Jacob and Jacques Monod, whom he credits in part for inspiring his interest in molecular biology. Tonegawa graduated from Kyoto University in 1963 and, due to limited options for molecular biology study in Japan at the time, moved to the University of California, San Diego to do his doctorate study under Dr. Masaki Hayashi. He received his Ph.D. in 1968.

Tonegawa conducted post-doctoral work at the Salk Institute in San Diego in the laboratory of Renato Dulbecco. With encouragement from Dr. Dulbecco, Tonegawa moved to the Basel Institute for Immunology in Basel, Switzerland in 1971, where he transitioned from molecular biology into immunology studies and carried out his landmark immunology studies.

In 1981, Tonegawa became a professor at the Massachusetts Institute of Technology. In 1994, he was appointed as the first Director of the MIT Center for Learning and Memory, which developed under his guidance into The Picower Institute for Learning and Memory. Tonegawa resigned his directorship in 2006 and currently serves as a Picower Professor of Neuroscience and Biology and a Howard Hughes Medical Institute Investigator.

Shortly following his Nobel Prize in 1990, Tonegawa again changed fields from immunology to neuroscience, where he has focused his research in the ensuing years.

Tonegawa is a fan of the Boston Red Sox, and threw out an opening pitch during their 2004 World Series championship season.

Tonegawa also served as Director of the RIKEN Brain Science Institute from 2009 to 2017.

Tonegawa was an early adopter of optogenetics and biotechnology in neuroscience research, leading to his groundbreaking work identifying and manipulating memory engram cells. In 2012, his lab demonstrated that the activation of a specific sub-population of mouse hippocampal neurons, labelled during a fear conditioning paradigm, is sufficient to evoke a behavioral response correlated with a precise memory trace. This confirmed for the first time that memory information is stored in specific cellular ensembles in the hippocampus, now frequently called memory engram cells.

More recently, his lab continues to employ optogenetic Technology and virus injection techniques to expand their findings on the engram cell ensemble. Notably, Tonegawa has uncovered the role of memory engram cell ensembles in memory valence, as well as their role in brain disorders such as depression, amnesia, and Alzheimer’s disease. These works provide proofs of concept for Future medical treatments in humans through the manipulation of memory engram ensembles.