Evaluation of: Flaherty KT, Infante JR, Daud A et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 367(18), 1694-1703 (2012). The treatment of metastatic melanoma with BRAF inhibitors initially gave dramatic results compared with standard chemotherapy with significant progression-free survival times. Unfortunately, within a matter of months, the melanomas become refractory to anti-BRAF-Targeted therapy and some patients experience toxicity in the form of primary cutaneous squamous cell carcinomas. While recent reports of dual therapy targeting the MAPK pathway (e.g., dabrafenib and trametinib) show increased response rates and less toxicity, it is not apparent that overall survival has been significantly impacted. While targeted therapy has significantly altered the management of melanoma, novel approaches and strategies will likely have to be employed to counter melanoma cell heterogeneity and the selection of resistant clones. © 2013 2013 Expert Reviews Ltd.