Melanoma is the third most common skin cancer but accounts for the majority of skin cancer-related mortality. The rapidly rising incidence and younger age at diagnosis has made melanoma a leading cause of lost productive years of life and has increased the urgency of finding improved adjuvant therapy for melanoma. Interferon-α was approved for the adjuvant treatment of resected high-risk melanoma following studies that demonstrated improvements in relapse-free survival and overall survival that were commenced nearly 30 years ago. The clinical benefits associated with this agent have been consistently observed across multiple studies and meta-analyses in terms of relapse rate, and to a smaller and less-consistent degree, mortality. However, significant toxicity and lack of prognostic and/or predictive biomarkers that would allow greater risk–benefit ratio have limited the more widespread adoption of this modality. Recent success with targeted agents directed against components of the MAP-kinase pathway and checkpoint inhibitors have transformed the treatment landscape in metastatic disease. Current research efforts are centered around discovering predictive/prognostic biomarkers and exploring the options for more effective regimens, either singly or in combination.