The interferons are complex proteins that have been widely tested as therapy for neoplastic diseases. Interferon (IFN)-alpha has been the most extensively studied in melanoma. It produces responses in about 16% of metastatic melanomas, about one third of which are complete. It has been combined with chemotherapy and biologic therapy in an attempt to improve on this response rate, but despite encouraging reports from single-institution trials, firm evidence for improved efficacy is still forthcoming. Randomized trials of sequenced biochemotherapies should shed further light on this issue. The outlook in the adjuvant setting is much brighter with the recently reported positive results of the European Cooperative Oncology Group trial E1684 that showed improved overall and disease-free survival for high-risk patients treated with IFN-alpha. The lack of efficacy of lower dosages and different schedules of administration argues for the use of maximally tolerated doses. IFN-gamma has proved disappointing in cases of both metastatic and high risk for relapse melanoma, but has been effective in locoregional disease, particularly in combination with tumor necrosis factor-alpha and melphalan. Further research will need to focus on sequencing, improved methods of administration, and efforts to reduce toxicity.