Forty percent of patients with severe ulcerative colitis will fail to respond to intravenous corticosteroids. Cyclosporine and other calcineurin inhibitors offer an alternative to colectomy for these patients. Intravenous cyclosporine will induce remission within 14 days in 50-80% of patients who fail intravenous corticosteroids. The long-term response rates for responding patients are 40-60%. Subsequent maintenance therapy with azathioprine or 6-mercaptopurine is recommended at the present time, although the uncontrolled studies underlying this observation have yielded variable results. Toxicity occurs frequently in patients treated with high dose cyclosporine, and there is a small risk of opportunistic infection and death. Pilot studies have suggested that the microemulsion cyclosporine formulation Neoral and tacrolimus may also be of benefit in this patient population. Additional studies to determine the dose response of intravenous cyclosporine, to determine the role of azathioprine for maintenance, and to determine the efficacy of Neoral and tacrolimus are needed.