It is now well established that a subpopulation of tumor stem cells (TSCs) are present within cancer tissues. This suggests that tumors evolve from stem cells; however, the exact cell of tumor origin, the potential role of dedifferentiation, and the role of plasticity in tumor development are largely unknown. A model cancer for the study of the oncologic process is melanoma. The developmental biology of melanocytes is relatively well understood, the cells pigment as they differentiate making them easy to identify, and benign and malignant tumors develop on the skin surface allowing direct observation of growth features, early detection, and removal. This ready access to early-stage tumors will facilitate study of the early oncologic processes and the role of tissue stem cells. Melanomas, like other cancers, include a subpopulation of TSCs. These TSCs have access to embryologic developmental programs, including the capacity to differentiate along multiple cell lineages. For example, melanomas can activate germ–cell pathways with major implications for TSC self-renewal through the activation of telomerase and genomic instability through the collision of meiotic and mitotic pathways (meiomitosis). The TSC model is still evolving, but the existence of TSCs has significant ramifications for tumor development, diagnosis, prognosis, and treatment of melanoma and other cancers.