The past decade has revealed that melanoma is comprised of multiple subclasses that can be categorized on the basis of key features, including the clinical stage of disease, the oncogenic molecular 'drivers', the anatomical location or the behaviour of the primary lesion and the expression of specific biomarkers. Although exercises in subclassification are not new in oncology, progress in this area has produced both conceptual and clinical breakthroughs, which, for melanoma, are unprecedented in the modern history of the disease. This Review focuses on these recent striking advances in the strategy of molecularly targeted approaches to the therapy of melanoma in humans.