The incidence of melanoma has been continuously increasing in the last decades, and faster than any other cancers. Melanoma is the leading cause of death from skin disease. It is estimated that 76,690 Americans will be diagnosed with melanoma in 2013 and 9,480 will die from the disease. Molecular mechanisms underlying melanoma pathogenesis have been extensively studied and novel therapeutic weapons developed. BRAF and MEK pathways emerged as key players in this field. Recently, novel drugs such as vemurafenib, dabrafenib and trametinib were approved for treatment of advanced disease harbouring BRAF V600E and V600K mutations. In addition, an effective strategy to build upon the successes seen with dabrafenib and trametinib monotherapies has been to combine these agents (CombiDT), with the goal of further improving response rates and delaying resistance. Our review gives an overall point of view concerning BRAF and MEK pathways as well as the role of BRAF and MEK testing in directing the personalised treatment of patients with metastatic melanoma.