Cutaneous melanoma is a significant health problem worldwide. Available treatments can induce objective tumor regression in a small percent of patients, but these responses are not always associated with improved long-term survival. The resistance of melanoma to therapy and its predestined recurrence are related to the genetic heterogeneity and genomic instability of the tumor. For many years these genetic alterations were thought to be linked to the accumulation of random mutations in functionally differentiated cells which transform them into malignant cells that have lost their ability to differentiate and have acquired drug resistance. In the last few years it has been largely demonstrated that melanoma as other solid tumors contains a subpopulation of cells (CSCs) considered the source of the primary tumor mass, of new tumor nodules and responsible for drug resistance and cancer recurrence. In this review, we provide an overview of findings and advances in CSCs research that are relevant to the initiation, natural history, and the response to treatment of malignant melanoma.