Malignant melanoma is a deadly disease in which standard treatment options have remained remarkably static over the past 30 years. Recent discoveries have expanded the understanding of the molecular processes critical to melanomagenesis. During this same time period, therapeutic agents have been developed that target these processes, leading to an explosion of preclinical research. Several agents that have shown promise in the preclinical setting have now entered clinical trials. To date, the success of these molecularly targeted approaches as single agents has been limited. Although more encouraging results have been seen when these agents have been used in combination with cytotoxic therapy, the specific contribution of the targeted agents to the observed anti-tumor effects remains to be established in randomized controlled Phase III trials. This article presents a review of the limitations of current therapy, a description of key pathogenic mechanisms for which inhibitors exist and a summary of therapeutic trials of molecularly targeted agents in this disease.