In 1988 he started his own hedge fund, D. E. Shaw & Co, which employed proprietary algorithms for securities trading. In 2018, Forbes estimated his net worth at $6.2 billion. He is also a senior research fellow at the Center for Computational Biology and Bioinformatics at Columbia University, and an adjunct professor of biomedical informatics at Columbia's medical school. Shaw is chief scientist of D. E. Shaw Research, which conducts interdisciplinary research in the field of computational biochemistry.
According to the Institutional Investors Alpha magazines annual ranking for 2014, D. E. Shaw, who made $530 million in 2014, and  James H. Simons of Renaissance Technologies who made $1.2 billion were among the top 25 earners in the hedge fund industry. They are both "quantitative strategists who founded firms that build algorithms for trading."