Melanoma probably is the most aggressive cancer in humans and remains one of the leading causes of cancer death in developed countries. This review summarizes the most important alterations in protooncogenes and tumor suppressor genes that contribute to the pathogenesis of malignant melanoma, with a special emphasis on the involved signaling pathways. Our knowledge of the molecular biology of melanoma has been benefited from recent advances on high-throughput technologies analyzing wide genomic and gene expression profiles that have uncovered unknown candidate genes. To test the interactions between distinct pathways and of those with the environment a wealth of genetically modified animal models has been generated over the past years. Other studies have focused on the isolation of melanoma stem cells and on the characterization of signaling pathways that contribute to their survival and maintenance. A consequence of all these studies is the emergence of potential new strategies that could improve the still inadequate arsenal of therapeutic tools to fight against this fatal disease.