Until recently, the prognosis of patients with deep primary melanomas or regionally metastatic nodal disease has been poor, with 5-year survival rates of 25-50%. The results of the Eastern Cooperative Oncology Group (ECOG) trial 1684 represent the first evidence of effective adjuvant therapy for these patients. Interferon alfa-2b (IFN-alpha 2b) administered at maximally tolerated doses for 1 year significantly improved both relapse-free and overall survival. The impact of interferon therapy was observed early during treatment and the effect was durable. The results of this trial represent a breakthrough in the treatment of high-risk resected cutaneous melanoma and identify the new reference standard for new cytokines, vaccines and combinations. The favourable results provide a strong impetus for redoubled research into immunotherapy for treatment of melanoma. Specifically, ganglioside vaccines have been identified that induce antibody responses and may affect patient outcome and peptide/protein vaccines that are recognised by the T-cell have been identified in large numbers. ECOG and the U.S. Intergroup are conducting a phase III trial (E1694) that compares GM2 vaccine to IFN-alpha 2b and a phase II trial evaluating concurrent or sequential use of interferon and vaccines for patients with resectable melanoma. They are also planning phase II trials of peptides for patients with metastatic unresectable melanoma. Laboratory analyses of the immune responses induced by IFN and the several vaccines are anticipated to reveal the fundamental immune mechanisms that are important for relapse-free survival and immunological control of melanoma.