The protection of the body's stem cells from damage or death due to toxins is a critical function of an organism, as the stem cells need to remain intact for the entire life of the organism. One of the principal mechanisms for protecting stem cells is through the expression of multifunctional efflux transporters from the ATP-binding cassette (ABC) gene family. These same transporters have been known for over 25 years to also play a role in multidrug resistance of tumor cells. An exciting outcome of the concept of the cancer stem cell is that the tumor initiating cell may be innately resistant to many standard therapies. This provides one mechanism in which cancer stem cells could survive cytotoxic or targeted therapies and lead to tumor regrowth or relapse. Gaining a better insight into the mechanisms of stem cell resistance to chemotherapy might therefore lead to new therapeutic targets and better anti-cancer strategies.