Melanoma develops through a series of architectural and phenotypically distinct stages and becomes progressively aggressive, culminating in a metastatic disease. Considerable progress has been made in understanding the biological, pathological and immunological aspects of human melanoma progression. However, the diagnosis, prognosis and treatment of melanoma remain challenging tasks owing to the heterogeneous and complex nature of the molecular aberrations. By incorporating new molecular technology, key genes, involving signal pathways of malignant transformation and progression, continue to be uncovered. This revolutionizes current concepts of melanoma etiology and pathogenesis and introduces the most current diagnostic and prognostic techniques, as well as potential therapeutic approaches. A significant breakthrough is the discovery of the key role of the BRAF mutation in melanoma development and progression, including the most important signal pathway during melanoma development, the MAPK pathway. Additionally, the loss of homeostatic control of the melanocyte in the skin is the key event during melanoma progression. Thus, deregulated homeostatic control in the skin’s cellular microenvironment occurs through alterations in the expression of specific proteins. These proteins include growth factors and their receptors, adhesion molecules and their ligands, proteases and their substrates and transcription factors and their target genes. This article discusses the most recent advances in molecular diagnosis, prognosis and treatment of melanoma that will potentially benefit patients with this disease.