A workshop was convened by the AACR to discuss the rapidly emerging cancer stem cell model for tumor development and progression. The meeting participants were charged with evaluating data suggesting that cancers develop from a small subset of cells with self-renewal properties analogous to organ stem cells. Indeed, one critical question contemplated at the Workshop was whether tumors derive from organ stem cells that retain selfrenewal properties but acquire epigenetic and genetic changes required for tumorigenicity or whether tumor stem cells are proliferative progenitors that acquire self-renewal capacity. Of course, both mechanisms may occur and may depend on the organ site. Either mechanism is different from the widely held notion that most cells in a tumor should be competent for tumor formation. If the cancer stem cell model is correct and if such cells retain the hallmarks of some tissue stem cells in being rare and entering the cell cycle infrequently, they could constitute a population that is intrinsically resistant to current therapies designed to kill cycling cells. The participants critically discussed the need for a precise definition of cancer stem cells, the requirement for new markers and more rapid and tractable in vitro and in vivo assays, and the need to develop drug screening strategies to selectively target cancer stem cells to generate therapeutics for this subpopulation of cells that could be resistant to classic treatments while possessing potent tumor-forming capacity.