Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and even fewer experience durable survival benefit. These poor results come from treating melanoma as a single homogeneous disease. Recently, it has been shown that targeting activated tyrosine kinases (oncogenes) can mediate striking clinical benefits in several cancers. In 2002, a mutation at the V600E amino acid of the BRAF serine/threonine kinase was described as present in over 50% of melanomas. The mutation appeared to confer a dependency by the melanoma cancer cell on its activation of the MAP kinase pathway. The frequency and specificity of this mutation (95% at V600E of BRAF) suggests that it may be a potential target for therapy, and recent results with one inhibitor, PLX4032/RG7204, bare this out. This review updates the status of BRAF inhibitors in melanoma and what may be on the horizon.