This special issue of Journal of Clinical Oncology is devoted to the emerging field of cancer stem cells (CSCs). The goal of this article is to introduce general concepts of CSC biology to clinicians, and to provide a framework for their understanding the CSC-based approach to the development of novel diagnostics, therapeutics, and prevention strategies in oncology. This new approach differs from the traditional one because the latter is based on the long-held concept that tumor formation and growth are due to increased proliferation of cells in cancers compared with normal tissues. This traditional view is supported by molecular oncology research during the last 50 years, which showed that tumors undergo a series of genetic events (mutations) that result in the activation or overexpression of genes promoting proliferation (eg, oncogenes), the silencing of genes involved in inhibition of proliferation (eg, tumor suppressor genes), and the development of the ability of cancer cells to elude apoptosis. The consequence is the development and unchecked growth of tumors and their progression to metastases. Based on this traditional concept of tumor growth, it has been disappointing that therapies designed to kill proliferating cells often fail to cure cancer patients. Furthermore, during tumor development, tissues accumulate a series of mutations over years or even decades, but, because of tissue renewal, most cells in tissues are lost or eliminated in just a brief time, typically days or weeks, and with their loss, any mutations they have acquired would also be lost. Thus, new mechanisms need to be considered to explain human tumorigenesis. One explanation is that tumorigenic mutations occur in cells that are few in number but reside long term in tissues. But that is not sufficient to explain tumorigenesis. To be truly tumorigenic, this population of rare, mutated cells would have to self-renew, clonally expand, and acquire additional mutations. It is now widely believed that these long-lived, uncommon cells are tissue stem cells (SCs) or cells derived from them that acquire the ability to self-renew. When mutated, they can become CSCs. Both normal SCs and CSCs may account for only a small fraction of cells ( 1%) in any given tissue or tumor. By definition, SCs are self-renewing. Mounting evidence presented in the articles in this special issue suggests that CSCs initiate and drive tumor growth. This is nothing less than a paradigm shift. It is a shift to the view that, first, cancers originate in tissue stem or progenitor cells through dysregulation of the self-renewal process. Second, throughout tumorigenesis, CSCs drive tumor growth. Third, current chemotherapeutic agents and radiation therapy largely target proliferating and differentiated cells that form the bulk of the tumor but not the relatively quiescent CSCs. Also, SCs are drug resistant and CSCs appear to be so too. Thus, this quiescence and resistance may account for many treatment failures. Fourth, if this is the case, then the only effective way to treat cancer is to target the CSC population. Although this view may seem novel, the basic idea that SCs are the cells of clonal origin of malignancies has existed for at least several decades, if not longer, particularly for leukemias and teratomas. Early attempts—beginning in the 1970s—to directly measure SCs in tumors used several approaches. One was mousespleen colony assays (eg, injection of lymphoma cells into mice with the appearance of lymphoma colonies in the spleen). A second was the counting of metastatic lung colonies after intravenous inoculation of tumor cells into mice. A third was tumor colony formation in vitro. However, this latter method produced mixed results for human tumors. SCs have also been known for decades to radiation biologists. More recent evidence, as presented in the articles in this special issue, supports an SC origin for solid tumors as well. In the following paragraphs, we discuss the properties of normal SCs and CSCs, and their possible roles in carcinogenesis and in mediating tumor behavior.