The treatment of advanced melanoma underwent a complete revolution over the last years. Targeted therapy and immunotherapy marked the beginning of a new management model for cancer. Targeted therapies are drugs directed exclusively against specific molecules in order to modulate their action. Immunotherapy, on the other hand, operates through drugs aimed to restoring the normal anti-tumor activity of the immune system. Indeed, in pathological conditions the immune system could be silenced or avoided through several mechanisms of "immunological escape". Since Food and Drug Administration (FDA) approval of ipilimumab in 2011, many other molecules have been investigated. Recently, anti-PD-1 (nivolumab and pembrolizumab) achieved promising results. The aim of this review is to trace the history of nivolumab, through major Phase I, II and III studies until FDA and European Medicines Agency approval.