Interleukin-2 (IL-2, Proleukin) is one of the most effective agents in the treatment of metastatic renal cell carcinoma and metastatic melanoma. High-dose IL-2 therapy produces overall response rates of 15% to 20%; however, it is associated with significant toxicities that affect essentially every organ system. Although IL-2-related toxicities are usually reversible with therapy discontinuation, alternative IL-2 regimens have been evaluated. Several phase II studies have demonstrated that administering lower doses of IL-2 by IV bolus or continuous IV infusion or subcutaneously produces overall response rates similar to those with high-dose IL-2 therapy; however, randomized clinical trials have not yet been completed. In renal cell carcinoma, combining IL-2 with interferon alfa (Intron A, Roferon-A) or chemotherapy agents produces similar or increased overall response rates compared with the response rates of IL-2 alone, with no survival advantage. Combination IL-2 regimens in metastatic melanoma patients have produced variable results. The most promising regimens have included various IL-2-based biochemotherapy regimens in other patients. Randomized studies confirming the superiority of these regimens over high-dose IL-2 therapy are needed.