This review summarizes results from major recent trials regarding novel therapeutic agents in melanoma. The topics discussed include targeted therapy with BRAF (V-RAF murine sarcoma viral oncogene homolog B) inhibitors (vemurafenib and dabrafenib), MEK (mitogen-activated protein kinase kinase) inhibitors (trametinib), bcr-abl/c-kit/PDGF-R inhibitors (imatinib), and angiogenesis inhibitors (bevacizumab and aflibercept), as well as immunotherapy with anti-CTLA-4 (anti-cytotoxic T-lymphocyte antigen-4) antibodies (ipilimumab), anti-PD (anti-programmed death receptor) antibodies (nivolumab and lambrolizumab), and anti-PD-L (anti-programmed death ligand) antibodies. Various combinations of these agents, as well as adjunctive GM-CSF (granulocyte-macrophage colony-stimulating factor), T-VEC (talimogene laherparepvec) oncolytic viruses, and novel chemotherapeutic agents, are also described. Despite the tremendous advances that these novel treatments have created, optimal therapeutic agent selection remains a highly individualized decision. Melanoma therapy has vastly progressed since the days when dacarbazine was the sole option for advanced melanoma patients. The molecular understanding of melanoma pathogenesis has yielded a brighter future for advanced melanoma patients.