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An improved understanding of the clinical behavior and molecular biology of melanoma has led to multiple practice-changing advancements in recent decades. Nevertheless, the gold standard for primary melanoma treatment, in most cases, continues to be complete surgical removal of the tumor with a wide excision. Data from multiple prospective randomized trials have led to the development of evidence-based clinical recommendations for melanoma resection margins that are based on a lesion’s Breslow depth. Although resection presents the most effective means of local disease control, some patients are not surgical candidates for a variety of anatomic, cosmetic, or medical reasons. These patients may benefit from non-operative treatment options, which including topical therapies, intralesional injections, radiation therapy, and systemic therapy.