Cutaneous melanoma is the most aggressive skin cancer. Beside surgery, it is treated with chemotherapy and immunotherapy. However, many patients relapse after adjuvant therapy. The recent identification of several key molecular pathways implicated in the pathogenesis of melanoma is spreading development of a number of new translational targeted therapies which could play an important role in overcoming or minimizing resistance to chemotherapeutic drugs and proapoptotic therapies. This review summarizes environmental factors and the most significant molecular events involved in melanoma pathogenesis, disclosing mechanisms responsible for drug resistance and pointing out the clinical view for emerging targeted therapies. Standard therapies and an update on the current clinical trials are also described.