Renal cell carcinoma (RCC) has remained refractory to substantive change of its natural history despite intervention with a number of therapeutic modalities. Alpha interferons leukocyte interferon alpha [HuIFN-alpha (Le)] and lymphoblastoid interferon alpha [HuIFN-alpha (Ly)] initially were shown to produce regressions of metastatic renal cancers in approximately 25% of patients. Trials with recombinant alpha interferons have demonstrated response rates similar to those observed with natural interferons and have documented that the effect is due to the interferon molecule. Responses with interferons beta and gamma also have been observed, although it is too early to estimate response rates. The interpretation of response rates with interferon is confounded by the rare spontaneous regression of RCC. Responses appear to be delayed (mean response, 3-4 months) relative to those seen in patients with tumors responsive to chemotherapy. A subset of patients with slowly progressive disease may be more likely to to respond. Other patient characteristics predictive of response have not been well characterized. Questions of optimal dose and schedule remain unresolved for both natural and recombinant interferons. Trials of interferon combinations, interferon and chemotherapeutic agents, and interferon administered with other biological-response modifiers are under way. The availability of recombinant interferons should facilitate the isolation and correlation of laboratory and clinical effects.