Metastatic melanoma is notoriously one of the most difficult cancers to treat. Although many therapeutic regimens have been tested, very few achieve response rates greater than 25%. Given the rising incidence of melanoma and the paucity of effective treatments, there is much hope and excitement in leveraging recent genetic and molecular insights for therapeutic advantage. Over the past 30 years, elegant studies by many groups have helped decipher the complex genetic networks involved in melanoma proliferation, progression and survival, as well as several genes involved in melanocyte development and survival. Many of these oncogenic loci and pathways have become crucial targets for pharmacological development. In this article we review: (1) our current understanding of melanoma genetics within the context of signaling networks; (2) targeted therapies, including an extensive discussion of promising agents that act in the Bcl-2 signaling network; (3) future areas of research.