Despite the use of a variety of cytotoxic and immunotherapeutic agents in adjuvant trials in patients following resection of high-risk early cutaneous melanoma, only interferon-alpha2b (IFN-alpha) has shown reproducible efficacy. High-dose IFN-alpha (HDI) is superior to observation in prolonging relapse-free survival. There is still no formal proof of a statistically significant advantage of HDI in prolonging overall survival. For this reason the continued use of observation-only control arms is justified and desirable in adjuvant melanoma trials, and, wherever possible, patients with resected high-risk and intermediate-risk melanoma should be entered on these studies. The toxicity of HDI is high, but the majority of patients complete treatment with dose modification and nearly all toxicity is rapidly reversible. There is now a useful body of information on the supportive care of patients receiving HDI, and data on cost and quality-adjusted time without symptoms and toxicity (Q-TwiST) to support its use in certain high-risk patients. Interim results from a trial of intermediate-dose IFN-alpha are promising. These, and ongoing studies of pegylated IFN-alpha, and of shorter induction-only HDI promise refinements in treatment which may improve efficacy:toxicity ratios.