Stage III melanoma, defined as regionally advanced disease based on the presence of either microscopic or gross lymph node involvement, remains a challenge for clinicians to treat secondary to the limited therapies that have clearly shown any benefit in overall survival compared with observation alone. The US FDA approved peginterferon alfa-2b (pegIFN alfa-2b) in March 2010 for use in the adjuvant setting to treat stage III malignant melanoma. The approval of pegIFN alfa-2b was based on results from the EORTC 18991 trial, which showed pegIFN alfa-2b had superior relapse-free survival compared with observation alone. PegIFN alfa-2b is administered subcutaneously and, aside from the nonpegylated IFN-α, is the only systemic therapy approved by the FDA to treat stage III melanoma. In this review, emphasis will be placed on describing the history of the use of IFN-α in regionally advanced melanoma, with a primary focus on the efficacy and safety profile of pegIFN alfa-2b as an adjuvant therapy in treating malignant melanoma.