The therapeutic landscape for cutaneous melanoma has dramatically advanced in the last several years with the development, validation, and approval by the US Food and Drug Administration of several new therapies that have proven effective in treating metastatic disease. Considerable effort has been put into identifying prognostic and predictive markers of therapeutic response to better delineate the patient populations most likely to benefit from treatment. Baseline tumor burden has been described as a common clinical factor associated with treatment response: lower tumor burden at the time of therapeutic intervention is associated with improved responses and survival outcomes on several therapies. Some therapies have shown efficacy as adjuvant interventions in patients with subclinical disease following definitive treatment, further supporting their role in patients with minimal tumor burden. The increasing evidence that patients with lower tumor burden may be the ones who derive maximal benefit from several melanoma-directed therapies points toward the critical need for risk-tailored surveillance to permit early identification of melanoma metastasis in patients at high risk for recurrence.