Gottesman founded the investment advisory firm First Manhattan Co. in 1964. He began a friendship with Warren Buffett in 1962. He was an early investor in Berkshire Hathaway and today owns 16,100 shares (class A), worth $3.5 billion in 2015. He joined the Berkshire Hathaway board of Directors in 2003. In 2008, Gottesman donated $25 million to the Yeshiva University Medical School. This gift was used to form the Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine, which operates as a stem cell research center.