Immune checkpoint inhibitors and MAP kinase pathway targeted therapies have revolutionized the management of advanced melanoma, and significantly prolong the overall survival of patients with this disease. The 1-year survival now exceeds 70%, yet <50% of patients are alive at 3 years for both single agent anti-PD-1 therapy and combined MAP Kinase targeted therapy. Of greatest urgency is an understanding of the biology of response and resistance, so that novel combinations are optimised, toxic combinations are reserved for those who need them, and therapy changes can be made early during the course of the disease.