While cancer treatment modalities are gradually improving due to increased knowledge about tumor heterogeneity and the cancer stem cell hypothesis, there remains a disconnect between tumor detection and mortality rates. The increasing knowledge of stem cell biology and its contribution to cancer progression illuminates the potential for chemopreventative regimens that effectively target the tissue-specific stem cell. Several signaling pathways have emerged that are critical for regulating stem cell self-renewal and multilineage differentiation over a range of tissue types, including Wnt, Hedgehog, and Notch signaling. Dysregulation of these genes can lead to cancer, which supports the cancer stem cell hypothesis. Several known chemopreventative agents have recently been shown to impact these and other pathways in the stem cell population, suggesting that their efficacies may be attributed in part to maintaining homeostasis of tissue-specific stem cells. Further understanding of the mechanisms of action of chemopreventative agents and of stem cell biology will generate better chemoprevention regimens that can be recommended especially to those in high-risk populations.