Metastatic renal cell carcinoma (MRCC) represents an immunoresponsive malignancy in individual patients. Interferons (IFNs) have thus been broadly investigated in this cancer type, with the most commonly used being recombinant IFN-alpha. The average response rate is 15%, with a response duration of 4 to 6 months. Complete responses are rare (< or =5%), but may be long-lasting. Responses are seen predominantly in lung and lymph node metastases. Subcutaneous (SC) or intramuscular (IM) doses of 9 to 10 x 10(6) U/d or 9 to 18 x 10(6) U thrice weekly are most often used. Flu-like symptoms (fever, myalgia, asthenia) occur in almost all patients treated with IFN-alpha and may be dose-limiting. The combination of IFN-alpha with vinblastine is not superior to IFN monotherapy. Phase III studies have demonstrated a modest survival benefit for IFN-alpha therapy as compared with placebo-equivalent treatment, with a survival gain of 3 to 7 months. Predictive for beneficial outcome are an excellent performance status, low sedimentation rate, no weight loss, and long interval between initial diagnosis and start of IFN treatment. The significance of nephrectomy is currently being investigated in phase III studies. IFN-gamma has no major therapeutic role in MRCC. IFN-beta and "natural IFN" are equally effective as IFN-alpha. In conclusion, IFN-alpha represents the standard treatment in patients with MRCC who are candidates for systemic therapy. Any IFN-alpha-containing combination treatment is investigational (eg, with interleukins or retinoids).