Interest in immune-modulating neoadjuvant therapy for melanoma is growing. It is possible that BRAF/MEK inhibition will be more effective in the neoadjuvant than in the adjuvant setting because of the effect of the tumor biomass. And the benefits neoadjuvant therapy would offer in assessing biologic response assessment to treatment are significant. In this review the authors discuss the rationale for this treatment approach, summarize completed and ongoing neoadjuvant clinical trials, and contextualize these findings within the growing body of knowledge about targeted and immune checkpoint therapy.