Next-generation sequencing (NGS) has provided significant insights into the pathogenesis of human malignancies. In advanced melanoma, two therapeutic avenues have appeared and have immediately become the standard of care, i.e. targeted therapy with small molecule inhibitors, and immune checkpoint blockade. Sequencing has always been essential for determining which patients may benefit from targeted therapies (e.g. the presence of BRAF mutations). While sequencing does not currently help recognize which patients might benefit from immune checkpoint blockade, recent data suggest that this may change. Multiple studies have identified tumor mutation profiles associated with patients benefiting from immune checkpoint blockade therapy. These findings suggest comprehensive tumor sequencing may become a critical step for predicting therapy responses to all systemic therapies. In this review, the current and potential future impact of NGS on treatment decisions in advanced melanoma will be summarized and discussed.