Cancer is being increasingly recognized as a very heterogeneous disease, both within an individual tumor and within a tumor type and among tumor types. This heterogeneity is manifested both at the genetic and phenotypic level and determines the progression of disease and response to therapy. It is possible to see the heterogeneity in examples of differential disease progression and response to therapy of the same tumor type, as morphology does not always reveal underlying biology. The diagnosis of tumors by histopathological and morphological criteria cannot fully account for the variability seen in prognosis and therapy outcome. Here we review some recent concepts that have emerged from the genetic analysis of metastatic melanoma.