Central to the debate about cancer stem cells in solid tumors is the proportion of cells that can initiate, propagate, and re-initiate tumors. An initially assumed minor subpopulation is confronted with recent data suggesting as many as 30% of primary tumor cells have stem cell characteristics. This review discusses quantitative modeling studies that augment our understanding of stem and non-stem cancer cell interactions during tumor progression and the resulting fraction of cancer stem cells. A discussion of how these findings can be carefully evaluated in novel, integrated interdisciplinary studies is offered.