Incidence of melanoma has been increasing in both sexes in the last decades. Advanced melanoma has always been one of the deadliest cancers worldwide due to his high metastatic capacity. In the last ten years, progresses in the knowledge of the molecular mechanisms involved in the melanoma development and progression, and in immune-response against melanoma, empowered the development of two new classes of systemic therapeutic agents: target-therapies and immunotherapies. Both classes consist of monoclonal antibodies inhibiting specific molecules. Target-therapies are selectively directed against cells harboring the BRAFV600-mutation, while immunotherapies target the two molecules involved in immune-checkpoint regulation, enhancing the immune response against the tumor: cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 receptor (PD-1). Target- and immunotherapy demonstrated to improve both progression-free and overall survival in melanoma patients either in metastatic or in adjuvant settings. Several drugs have been approved in recent years as monotherapy or in combination, and many other drugs are currently under investigation in clinical trials. In the current review on new systemic therapies for cutaneous melanoma, we revised the molecular basis and the mechanisms of actions of both target- and immunotherapy (why). We discussed who are the best candidate to receive such therapies in both the adjuvant and metastatic setting (who) and which were the most important efficacy and safety data on these drugs (what).