The evolution of a cancer in a tissue is shown. Tissues in which a cancer arises have a cellular hierarchy in which a stem cell gives rise to the mature cells of a tissue. A specific niche supplies signals needed for stem cells to maintain themselves through a process called self renewal. Since the stem cells are often the only longlived cells in a tissue, the initial mutations that lead to a cancer accumulate in the stem cells. The final mutation that culminates in frank malignancy could either enable a cancer cell that arose from a stem cell to escape constraints on its expansion or, if from a progenitor cell, gain the ability to self renew. Regardless of the cell of origin, recent evidence strongly suggests that many tumors contain a minority cell population exhibiting hallmarks of “cancer stem cells” in that they appear to self-renew and give rise to multiple tumor cell lineages when grown as xenografts. How further mutations that arise as a result of genomic instability affect the number or cell-of-origin of cancer stem cells in tumors is not clear. Furthermore, how these ongoing oncogenic mutations affect the dependence of the now-cancerous self-renewing cell on a normal or altered niche is unknown. Understanding the mechanisms that permit abnormal self-renewal could lead to cancer therapeutics that target the cancer stem cells that may be intrinsically resistant to contemporary cytotoxic agents. Illustration by Jamie Simon, Salk Institute, La Jolla, CA. For details, see the article by Clarke et al. on page 9339 of this issue.