Melanoma is a neoplasm of rising incidence, especially in people under 35 years of age. It is a neoplasm for which we lack effective treatments after failure of definitive surgery. The strong rationale for immunologic intervention and encouraging early results obtained with recombinant interferons in multiple trials of patients with advanced melanoma are reviewed. Criteria for evaluation of response to interferons, which ideally include a minimum treatment duration of 3 months, liken this modality to endocrine therapy of other cancers. Objective regression has been obtained in 20% of patients entered into trials of recombinant interferon alfa-2a and alpha-2b. More interestingly, the fraction of all responses with alfa-2a and alfa-2b that are complete responses is nearly one third; these complete responses have proven to be extremely durable (1 + to 3+ years) in several independent trials. Trials in progress to determine the effects of recombinant alpha interferons in the adjuvant setting of high-risk stage II (lymph node metastatic) or stage I (deep primary) melanoma are noted. The rationale and trial designs for combined trials of interferons of different types (alpha or beta plus gamma), interferons plus more tumor-specific antibodies, and interferon-chemotherapy combinations are presented. Recombinant interferons have achieved a place in the developmental armamentarium of medical oncology for melanoma--and phase III trials to compare the relative effects of decarbazine or semustine and interferon alpha are under way. The challenge now is to understand the mechanism of action for interferons, which may optimize the effects of the substance alone, and for interferon use in combination with other agents, such as antibodies, whose effects may be enhanced when used in conjunction with interferon treatment.