The last decade has seen a considerable improvement in the understanding of the biology of melanoma. Advances have come in the understanding of the importance of critical oncogenes and tumour suppressor genes, epigenetic phenomena, signalling pathways, drug resistance mechanisms, the pivotal role of the local immune system, and the importance of cell-cell and cell-matrix interactions. Many of these pathways and interactions include potentially 'drugable' targets. These developments have allowed the identification and/or design of a range of new, targeted therapies. Evaluation of these new drugs has brought a whole new series of challenges. These include identification of appropriate pre-clinical models, overcoming the redundancy in-built in complex biological systems, identification of appropriate molecular and clinical endpoints to show that the drug is hitting the target, how to combine treatments, and new toxicities. For the first time, there is the possibility of personalized treatment for melanoma patients, based on individual host and tumour characteristics. This paper discusses the range of new drugs and targets have been identified, the outcome of clinical trials, and the directions for future advances.