Metastatic melanoma has a poor prognosis; the median survival for patients with stage IV melanoma ranges from 8 to 18 months after diagnosis. Interferon-α provides significant improvement in disease-free survival at the cost of poor tolerability. Identifying patients who benefit the most may improve the cost:benefit ratio. In addition, no data exist for the role of adjuvant therapy in noncutaneous melanoma. Molecular profiles may help to identify patients who benefit the most from adjuvant interferon therapy. In this review, the American Joint Commission on Cancer 2009 staging criteria and emerging biomarker data to guide adjuvant treatment decisions will be discussed. Several criteria to guide selection of patients are discussed in detail. These include Breslow thickness, number of positive lymph nodes, whether or not the primary lesion has ulcerated, immunologic markers, and cytokine profiles. Substantial progress has been made in deciding which patients benefit from interferon-α adjuvant therapy. Interferon-α is the only agent currently approved for the adjuvant treatment of this deadly disease, despite its side effect profile. More effective drugs with better tolerability are needed.