The incidence of melanoma has been rising steadily during the last four decades and is now among the highest of all human cancers. As for most tumors, malignancy and metastatic spreading represent the deadly aspects of a tumor that, if eradicated before becoming invasive, can be easily cured. In fact, melanoma metastatic to regional lymph nodes carries a poor prognosis, and distant metastatic melanoma becomes incurable. Because traditional forms of chemotherapy have little effect on this type of tumor, differentiation therapy has been considered as a possible alternative, based on the consideration that malignancy and differentiation are usually inversely related. However, the relationship between these two factors turned out to be more complex for melanoma cells, and in some murine model systems it has been found that differentiated cells, although less tumorigenic, could be even more metastatic. No clear correlation has been reported between (epi) genetic changes induced by differentiating drugs and the increased malignant phenotype. This review examines what is known to date about differentiation state and metastatic ability of melanomas, and also reports some novel data with the B16 mouse melanoma model system.