The transition from a normal to a neoplastic cell is a complex process and involves many sequential genetic events. Over the last several years, substantial progress has been made in the understanding of molecular biology of melanoma including its development, progression, and resistance to therapy. An important step in cancer development appears to be senescence — a crucial barrier that prevents the proliferation of cells that are at different stages of malignancy. This review is mainly focused on patterns of molecular changes in the different steps of neoplastic transformation in melanoma and provides an up-to-date view on our understanding of the molecular genetics of melanoma development as well as therapeutic approaches based on this knowledge.