The cancer stem cell (CSC) concept derives from the fact that cancers are dysregulated tissue clones whose continued propagation is vested in a biologically distinct subset of cells that are typically rare. This idea is not new, but has recently gained prominence because of advances in defining normal tissue hierarchies, a greater appreciation of the multistep nature of oncogenesis and improved methods to propagate primary human cancers in immunodeficient mice. As a result we have obtained new insights into why the CSC concept is not universally applicable, as well as a new basis for understanding the complex evolution, phenotypic heterogeneity and therapeutic challenges of many human cancers.