Surgery remains the principal treatment for local, regional and isolated metastatic melanoma. Adjuvant therapy is now available for patients with high risk of recurrence after surgical treatment but is controversial and inconsistently used around the world. In 1995, high-dose interferon-alpha 2b was approved by the FDA, providing clinicians with the first adjuvant therapy for use outside a clinical trial. In this review, we discuss surgical approaches to the management of the primary lesion and regional lymph nodes and the use of high-dose interferon. We will also provide guidelines for the use of interferon and discuss current clinical trials evaluating alternate forms of adjuvant therapy.