Notorious for its proclivity for metastases and resistance to known therapies, malignant melanoma represents a major health concern. Genetic, epidemiological and genomic investigations are highlighting a repertoire of stereotypical mutations that are associated with human melanoma genesis. The functional significance of many of these genetic alterations is being ascertained through the use of in vivo mouse models. Insights from human and mouse studies, coupled with the development of novel tools for high-resolution characterization of the melanoma genome, hold promise for the identification of better diagnostic markers and potential therapeutic targets. With the rapid improvements in drug design, these recent advances are generating optimism for the development of better therapeutic options for melanoma patients.