There has been a therapeutic revolution in the treatment of metastatic melanoma over the past decade. Patients presenting with inoperable disease have several therapeutic options, which can include both targeted and immune therapy. Immune checkpoint inhibitors have demonstrated an improvement in overall survival and led to some durable responses. However, toxicity, especially in combination regimens, can be severe. Adverse events should be anticipated, diagnosed as early as possible, monitored, and managed. Combination BRAF and MEK inhibition has also been shown to improve overall survival in patients with V600E-mutated melanoma. Responses to therapy are often rapid, and treatment is not associated with immune-related adverse events. Current trials are under way to determine which option is optimal as frontline therapy for patients with V600E melanoma. In patients with progressive disease despite standard therapies, clinical trials are recommended. There are several promising agents in development.