Metastatic melanoma continues to set a therapeutic difficulty for health professionals worldwide. In the past decade there have been great advances in melanoma therapy. Multiple new drugs and treatment modalities have been approved for use. The first big breakthrough in the field of melanoma therapy was as targeted therapies emerged, targeting the most frequently seen mutation in melanoma BRAFV600. These therapies changed both treatment strategies and research made for the treatment of unresectable or metastatic melanoma. These, however, as promising as they were, were soon to be found ineffective as single agents, since therapy resistance mechanisms emerged within tumors. The most recent advances are in the field of immunotherapy. Both CTLA-4 blockers and PD-1 blockers, as monoclonal antibodies, showed promising results for the treatment of melanoma, especially wildtype-melanoma, and now are under development for other cancers as well. The greatest promise seen these days for a successful cure of unresectable melanoma, lies in combination therapies. Both the combination of BRAF and MEK inhibitors, or the combination of CTLA-4 and PD-1 inhibitors have been shown to prolong progression free survival and overall survival as compared to monotherapies. This paper will review the major current pharmacologic types of treatment available nowadays for melanoma, with an emphasis on the seemingly promising approach of combining the different modalities of treatment for unresectable, stage III and IV malignant melanoma.