Melanoma is the most aggressive form of skin cancer. Unfortunately, despite recent improvements for some solid tumors, the prevalence and mortality of melanoma continue to increase. The identification of activating mutations in melanoma, combined with a growing appreciation of the different pattern of genetic changes in the anatomically defined melanoma subtypes, has become the focus of a concerted effort to translate these discoveries into personalized therapeutic approaches for this disease. This article reviews the known mutations, amplifications, and deletions in kinase signaling pathways that have been implicated in melanoma; the prevalence of these genetic events in clinicopathologically defined melanoma subtypes; and the results of clinical trials that use targeted therapy approaches to block aberrantly activated pathways resulting from these mutations. The challenges that must be overcome to achieve improved outcomes with targeted therapies in melanoma in the future are also discussed.