Despite intensive research and numerous clinical trials on the adjuvant treatment of patients with high-risk cutaneous melanoma, the issue is still controversial. Early positive results from studies on adjuvant chemo- and immunotherapy were based on historical controls and could not be confirmed by prospective randomized trials. The effect of interleukin-2 in the adjuvant treatment of malignant melanoma is not yet clearly defined. Combined treatment modalities like bio-chemotherapy are still to be analyzed in controlled clinical trials, and results of new studies with active specific immunization (vaccination) will only be available within the next years. Only interferon alpha (IFN alpha) has shown reproducible superiority over observation for high-risk melanoma patients in large prospective randomized trials with respect to disease-free survival (DFS) and partially for overall survival (OS). These studies resulted in the approval of IFN alpha for the adjuvant treatment of malignant melanoma in many countries. Low-dose IFN has shown significant prolongation of DFS, but so far failed to improve OS. The question whether high-dose IFN has shown enough superiority over observation with respect to OS based on one negative and two positive trials to make it the standard therapy in stage IIb,c and stage III melanoma patients still remains unanswered. Results from intermediate-dose IFN alpha, pegylated IFN alpha, and modified high-dose interferon schedules are pending. In conclusion, interferon is the cornerstone of adjuvant therapy in high-risk melanoma today, but the optimal dosage and duration of treatment are still to be defined. Patients with high-risk malignant melanoma should preferentially be treated in prospective randomized multicenter trials to give more detailed data for treatment recommendations.