Melanoma is an aggressive disease process, with a heterogeneous aetiology linked to environmental and genetic risk factor profiles. Overall prognosis for advanced disease remains poor, and a lack of effective systemic therapies has prompted investigation into alternative strategies. The identification of novel mutations that instigate and perpetuate melanocyte transformation has offered insight into new treatment approaches, and the subsequent development of targeted treatments appears to be integral to improving melanoma survival. This article reviews the mechanisms of melanoma oncogenesis and classic molecular signalling pathways, targeted treatment approaches based on the molecular model and immunotherapy, and the advent of next-generation sequencing technologies in understanding the complexity of the melanoma pathogenome. In addition to the known somatic activating mutations BRAF and NRAS, exome sequencing has recently identified RAC1, a novel UV-signature gain-of-function mutation. Germline mutations associated with familial melanoma have added a further dimension to the molecular underpinnings of melanoma, implicating BAP1 and MITF as melanoma predisposition genes. Advances in understanding melanoma and implementing targeted treatment strategies will be of increasing importance in this era of personalised medicine.