If untreated at early stages, melanoma becomes a highly aggressive cancer with rapid metastasis to distant sites. Although cell biologic analyses have uncovered a multitude of signaling pathways involved in melanoma genesis and progression – including the MAPK, PI3K, and FAK pathways – efficacious therapies that target these cellular components have remained elusive. Genome-wide technologies such as microarray chips and array comparative genomic hybridization have generated genetic information that can identify cellular mechanisms critical for the induction and maintainence of the malignant phenotype. Thus, such data can guide the choice of a biologically relevant drug. However, these techniques have also identified melanoma as a genetically and biologically highly heterogeneous disease that likely requires individually tailored therapies based on the patient¹s individual genetic and biologic alterations. In addition, these techniques have generated a large body of data on candidate melanoma genes that await extensive functional validation to separate so called “driver” from “passenger” events. In this review, we cover several advances in melanoma therapeutics and their current limitations as well as emerging genomic, proteomic, and epigenetic strategies for the identification of critical cellular dependencies that may be tractable to therapeutic targeting.