The last two decades have seen spectacular advances in our understanding of the biology of melanoma and, in particular, have elucidated the mechanisms operative in disease initiation and progression. With respect to the former, the genetics of melanoma and in particular the impact of genetic defects on dysregulation of the cell cycle are key issues in malignant transformation and are a major focus of this review. With respect to the latter, consideration also is given to the acquisition of growth factor autonomy and the capacity for invasion and metastasis from the standpoint of cell adhesion, motility, and matrix digestion. These events have specific morphologic correlates that will be briefly addressed. Where relevant, we will address certain of the modern pharmacogenetic strategies that flow from these novel observations concerning melanoma biology.