Noticing that the biotechnology company Genentech was conducting state-of-the-art research but not on diseases of the nervous system, he determined to get into the biotechnology Business. After rebuking Gilman's efforts to recruit him as an academic, he found a sponsor in George Sing, a venture capitalist at Merrill Lynch, and obtained $1 million in seed capital. He also recruited George Yancopoulos, a 28-year-old scientist, to be his partner, and in 1988 they founded Regeneron Pharmaceuticals. After several years of trying to recruit research doctors many of whom preferred to work in academia or for large corporations, they developed their first drug to treat Lou Gehrig’s disease. It was a failure as was their second drug to treat obesity. Thereafter, they invited the former Merck & Co. CEO Roy Vagelos to be the chairman of their company to help turn the company around. He implemented two strategic changes: only invest in drugs in which the biology of the disorder is fully understood; and do not underestimate the importance of human testing to ensure that what works in the laboratory will also work in the real world.

As CEO of Regeneron, Schleifer oversaw the "approval and growth of high-priced drugs." In 2011, Regereron's first successful drug was, Eylea, for age-related macular degeneration. Eylea prevented leaky blood vessels in the eye from causing blindness. He licensed the drug to Aventis which was then bought by Sanofi which had no interest in the eye drug. Sanofi, in order to get out of its commitment, paid Regeneron $50 million and ceded the rights back to Regeneron. The drug was a blockbuster generating $838 million in its first full year and sales increased 55% to $1.3 billion in 2013 making Schleifer a Billionaire. In 2014 Eylea grossed $1.735 billion.

As CEO Schleifer received a total compensation of $41,965,424 in 2014. According to the "annual collaborative report" from Equilar and The New York Times, Schleifer ranked 15th in the May 2015 list of "200 highest-paid CEOs of large publicly traded companies." He ranked first in the list of biopharmaceutical executives with the highest total compensation.