The incidence of melanoma has been increasing over the past twenty years. Unfortunately, the prognosis of advanced-stage disease is still poor. Advances have been made in the understanding of melanoma development and progression, resulting in the availability of promising novel therapeutic options. After the approval of ipilimumab, an immune checkpoint inhibitor of cytotoxic T-lymphocyte-associated antigen-4, and vemurafenib, a targeted v-raf murine sarcoma viral oncogene homolog B1 inhibitor, a new era for melanoma has started. Additional compounds, such as dabrafenib and trametinib, also received Food and Drug Administration approval recently and currently several other promising candidates, such as antibodies to programmed death-1, are under clinical development. Even though the novel compounds show impressive results as monotherapy, their efficacy may be enhanced in combination with other agents. In addition, combined treatment may reduce the chance of developing resistance. We review available clinical experience on approved therapies and discuss new developments. Furthermore, promising combination therapies are highlighted.