Melanoma is a main example of how applying advances in basic biology, pharmacology, and molecular diagnostics into the clinic results in unprecedented benefits to patients. After many years of lack of advances in the treatment of patients with metastatic melanoma, the advent of new therapies that block driver oncogenic signaling and modulate immune responses to cancer provided the first studies with a positive impact in overall survival (OS) of patients with advanced melanoma. The pace of progress in the treatment of this disease has been greatly accelerated by these initial breakthroughs, and it continues with new generation agents and combinatorial approaches.