Melanoma is the most aggressive form of skin cancer and advanced stages are inevitably resistant to conventional therapeutic agents. In particular, the inability of undergo apoptosis in response to chemotherapy and other external stimuli poses a selective advantage for tumor progression, metastasis formation as well as resistance to therapy in melanoma. Herein, we will review the molecular mechanisms of sensitivity and/or resistance of the most important drugs used in the treatment of melanoma. Furthermore, the novel strategies to overcome tumor chemoresistance will also be discussed. In particular, we will review the cancer stem cell hypothesis and how the failure of MDR reversal agents might increase the therapeutic index of substrate antineoplastic agents.