The discovery of CSCs in several types of solid tumors over the past few years represents a major paradigm shift in the field of oncology and is likely to change our understanding of the process of tumorigenesis. The existence of cancer stem cells also has direct therapeutic implications. Most current systemic therapies have been found ineffective in the treatment of solid tumors, and this may be due, at least in part, to increased resistance of the cancer stem cells. Selective pressure provided by treatment of the tumor with chemotherapy or ionizing radiation may allow for the survival and enrichment of a resistant CSC population, with subsequent reconstitution of the primary tumor with cells that will not be responsive to further treatment cycles. It will be important to understand how cancer stem cells are different from the rest of the tumor cell population in order to develop effective targeted therapeutics to this resistant cancer cell population, with the goal of improvement in patient outcomes.This article is part of the 2009 Cancer Chemotherapeutics special issue of Chemical Reviews.