ABCG2 is a member of the adenosine triphosphate-binding cassette (ABC) family of cell surface transport proteins. ABCG2 is expressed in many types of primitive repopulating cells, and may be a marker of tumor stem cells. The physiologic role of ABCG2 seems to be excretion of genotoxic substances from the body and from primitive repopulating cell populations. A unifying hypothesis is presented, linking the expression of ABCG2 in normal and malignant stem cells with a physiologic role for protection of stem cells. Future studies will explore the possible role of ABCG2 in tumor stem cells and how this may influence the selection of new cancer therapeutic strategies.