Progression from normal melanocyte to metastatic melanoma is a multistep, multigenic process. While relatively easy to conceptualize, the stages of melanoma progression are not necessarily discrete, nor are they unambiguously defined at the morphologic or molecular levels. The ability to stage the lesions more precisely would afford clinicians a greater confidence when designing therapeutic strategies. Unfortunately, a molecular definition of cells at each stage does not yet exist. Toward that end, the purpose of this review is twofold: (1) to highlight recent advances in our understanding of the molecular genetics of human cutaneous melanoma predisposition, and (2) to construct a molecular model of melanoma progression toward metastasis. © 1998 S. Karger AG, Basel.