The rapidly increasing incidence of melanoma, coupled with its highly aggressive metastatic nature, is of urgent concern. In order to design rational therapies, it is of critical importance to identify the genetic determinants that drive melanoma formation and progression. To date, signaling cascades emanating from the EGF receptor, c-MET and other receptors are known to be altered in melanoma. Important mutations in signaling molecules, such as BRAF and N-RAS, have been identified. In this review, some of the major genetic alterations and signaling pathways involved in melanoma will be discussed. Given the great deal of genetic heterogeneity observed in melanoma, it is likely that many more genetic determinants exist. Through the use of powerful genomic technologies, it is now possible to identify these additional genetic alterations in melanoma. A critical step in this analysis will be culling bystanders from functionally important drivers, as this will highlight genetic elements that will be promising therapeutic targets. Such technologies and the important points to consider in understanding the genetics of melanoma will be reviewed.