Cancer develops from normal tissues through the accumulation of genetic alterations that act in concert to confer malignant phenotypes. Although we have now identified some of the genes that when mutated initiate tumor formation and drive cancer progression, the identity of the cell population(s) susceptible to such transforming events remains undefined for the majority of human cancers. Recent work indicates that a small population of cells endowed with unique self-renewal properties and tumorigenic potential is present in some, and perhaps all, tumors. Although our understanding of the biology of these putative cancer stem cells remains rudimentary, the existence of such cells has implications for current conceptualizations of malignant transformation and therapeutic approaches to cancer.