Molecular testing of cancers to determine therapeutic eligibility is now standard of care and has changed the practice of pathology. Recent advances in the treatment of metastatic melanoma with BRAF and KIT inhibitors have increased the demand for molecular testing in melanoma. Furthermore, rapid progress is being made in determining potential new targets, mechanisms of resistance, and developing additional rationally designed therapies. The likely consequence will be a significant expansion of molecular testing for melanoma to include an array of multiple signaling intermediates. Currently, routine testing is mostly limited to BRAF and KIT. Mutations in these genes generally occur in a distinct group of melanoma subsets though, and with the numerous techniques available for mutation analysis, decisions about testing can be complex. The purpose of this review is to provide an overview of clinically relevant mutations which currently guide systemic therapy in Stage IV melanoma, how these molecular events vary with melanoma subtype and primary site of origin, and practical recommendations for testing. Diagn. Cytopathol. 2012;40:503–510. © 2012 Wiley Periodicals, Inc.