Much of what we know about the role of immunopathologic mechanisms in causing Crohn's disease and ulcerative colitis originated from research at The Mount Sinai Hospital. The authors were privileged to have been able to share in this undertaking, along with many others, including Moschcowitz, Klemperer, Otani, Crohn, Ginzburg, Oppenheimer, Garlock, Lyons, Marshak, Janowitz, Aufses, Waye, Greenstein, Sachar, Meyers, Gelernt, Mayer, Lichtiger and Kornbluth. In medical history, elucidation of disease processes is often serendipitous. Transplant surgery was successful because of the discovery by Hitchings and Elion of 6-mercaptopurine (6-MP) and azathioprine, which inhibited rejection. And the concept of immunosuppression slowly evolved into possible treatment of any disease thought to be caused by autoimmunity. This includes those diseases of the bowel seen so frequently at The Mount Sinai Hospital: ileitis, granulomatous colitis, ileocolitis, and ulcerative colitis. This paper depicts the progressive role of immunosuppressive drugs, from corticosteroids to 6-mercaptopurine, cyclosporine and anti-tumor necrosis factor, in both the treatment and understanding of the pathogenesis of Crohn's disease and ulcerative colitis. Major contributions to these treatments have come from physicians and surgeons with roots at The Mount Sinai Hospital.