Melanoma has been the most important cancer to drive immunotherapy development of solid tumors. Since 2010, immunotherapy has been revolutionized by the concept of breaking tolerance. It represents a major paradigm shift and marks the beginning of a new era. The impact of the first immune checkpoint inhibitors, anti–CTLA-4 and anti–PD-1/anti–PD-L1, is unprecedented. In 7 years, it transformed advanced-stage melanoma into a curable disease in over 50% of patients. Another major step has been the development of the combination of BRAF inhibitors plus MEK inhibitors in the treatment of BRAF-mutant melanomas. For the treatment of advanced disease, approvals were obtained for the immune checkpoint inhibitors ipilimumab (2011), nivolumab (2014), pembrolizumab (2014), the combination ipilimumab plus nivolumab (2015), and the oncolytic virus vaccine laherparepvec (2015). The combination dabrafenib plus trametinib for BRAF-mutant melanoma was approved in 2014, with similar success for other BRAF plus MEK inhibitor combinations. Because of its unique therapeutic index (high efficacy and low toxicity) anti–PD-1 agents (nivolumab and pembrolizumab) have now been placed at the center of practically all combination therapy development strategies in melanoma. Anti–PD-1 agents are the central molecule for combinations with a great variety of other immunotherapeutics such as immune checkpoint inhibitors, agonists, IDO inhibitors, macrophage polarizing agents, monoclonal antibodies, vaccines, targeted agents, chemotherapeutics, radiation therapy, and even microbiome modulators.