Melanoma is one of the most aggressive and treatment-resistant human cancers. 50 to 70% of melanomas carry BRAF mutations, with BRAFv600E being the most abundant. BRAF v600E which results in constitutively overactive MAPK/MEK/ERK signaling and melanocyte hyperproliferation, has been successfully exploited for targeted therapy. Selective RAF inhibitors such as vemurafenib or dabrafenib showed an unprecedented antitumor response rate in patients with BRAFv600e. Unfortunately, all patients rapidly acquire resistance to these drugs; relapse can be postponed -but not avoided- when BRAF inhibitors are combined with selective MEK1/MEK2-inhibitors such as trametinib. The difficulty in eradicating melanoma stems from its high degree of heterogenity and plasticit. Melanoma comprises heterogeneous subpopulations of cancer cells with different biological properties. Some of these may possess stem cell-like properties being able to self-renew and fuel tumor growth. Importantly, it has been proposed that melanoma stem/tumorigenic cells provide a reservoir of therapeutically resistant cells.