Treatment of metastatic renal cell carcinoma (RCC) remains unsatisfactory. To enhance the antitumor effects of various cytokines, combinations of these agents have been investigated. Interleukin-2 (IL-2) and interferon-alfa (IFN-alpha) have been combined based on data from preclinical studies suggesting synergism. A review of available phase I and II trials in more than 1,400 patients indicates that response rates are approximately 20%. Complete regressions are seen in 3% to 5% of patients. To demonstrate that this combination increases overall response rates, randomized trials were required. The results of a phase III study demonstrate a significantly improved response rate (18.6%) and 1-year event-free survival (20.9%) for patients treated with continuous infusion recombinant (r) IL-2 and subcutaneous IFN-alpha compared with either cytokine alone. The toxicity of rlL-2 and IFN-alpha is related to cytokine dose and schedule, but appears less than that reported with high-dose rIL-2. Analysis of prognostic factors and surrogate marker changes have been conducted. Performance status and number of disease sites predict response. rIL-2 and IFNalpha were then combined with fluorouracil, with initial reports suggesting response rates greater than 40%. Recent reports indicate 1% to 39% of patients responding. In a group of 836 patients with metastatic RCC receiving this therapy, 25.3% responded. Randomized trials comparing chemoimmunotherapy to rIL-2 and/or IFN-alpha are now required. The biologic basis and rationale for utilization of cytokines are strong. Clinical results are consistent with improved response rates in patients receiving rIL-2 and IFN-alpha. Continued investigation of novel and new treatment approaches remains a priority.