Metastatic melanoma beyond the regional nodes (American Joint Committee on Cancer stage IV) is a highly lethal disease. Few affected individuals survive beyond 5 years despite aggressive treatment. Clearly, effective adjuvant therapies to prevent the development of stage IV disease in at-risk patients are worthwhile and acceptable to patients, even if they are associated with significant toxicities. Improvements in our understanding of the prognosis and staging of melanoma have allowed us to better categorize patients based on their risk of developing metastatic disease, permitting the development of logical strategies using adjuvant therapies with toxicity profiles that are appropriate based on the level of risk for recurrence. Adherence to the standards of care for the surgical management of melanoma patients with high-risk primary disease or regional disease will help optimize the benefit that can be derived from adjuvant therapy. Clinical trials remain critically important as we seek to improve the outcome for melanoma patients, but for high-risk melanoma patients outside the context of clinical trials, adjuvant therapy with high-dose interferon-alfa2b should be considered a standard treatment option.