Over the past several decades, the incidence of melanoma has increased. Although surgery remains the primary treatment modality for localized early-stage lesions, melanoma is often diagnosed following locoregional and distant disease spread. Prognosis for advanced stage disease is dismal as one would expect; however, nowadays, the myriad of systemic therapies have allowed for improvements in disease free and overall survival. Such systemic treatment approaches include chemotherapy, immunotherapy, and molecularly targeted agents. Since the time of the approval of dacarbazine by the Food and Drug Administration for the treatment of metastatic melanoma in 1975, other agents have gained approval including interleukin-2, immune checkpoint inhibitors such as ipilimumab (anti-CTLA-4), and others. More recently, studies suggest that combination regimens of the aforementioned approaches may further improve outcomes when compared to monotherapy. Herein, the authors provide an up-to-date comprehensive review on the chemotherapeutic, immunologic, and molecularly targeted therapy approaches to the treatment of advanced melanoma.