Until recently, melanoma represented a significant clinical challenge to oncologists. However, the approval in 2011 of ipilimumab, an anti-CTLA4 monoclonal antibody, and vemurafenib, a BRAF inhibitor, completely changed melanoma management, with both drugs being shown to improve overall survival. The advent of these two drugs, together with the ongoing development of other targeted agents (e.g., MEK inhibitors) and immunotherapeutic compounds (e.g., anti-PD-L1), is providing the opportunity to trial new combination or sequential therapy approaches. Combined approaches of these new agents with surgery, radiotherapy and/or chemotherapy are also being assessed. Targeted agents in combination or in sequence with new immunotherapeutic compounds may represent the future, not only for the treatment of melanoma, but also for the treatment of cancer in general.