Although the concept of 'cancer stem cell' was first proposed more then a century ago, it has attracted a great deal of attention recently due to advances in stem cell biology, leading to the identification of these cells in a wide variety of human cancers. There is accumulating evidence that the resistance of cancer stem cells to many conventional therapies may account for the inability of these therapies to cure most metastatic cancers. The recent identification of stem cell markers and advances in stem cell biology have facilitated research in multiple aspects of cancer stem cell behavior. Stem cell subcomponents have now been identified in a number of human malignancies, including hematologic malignancies and tumors of the breast, prostate, brain, pancreas, head and neck, and colon. Furthermore, pathways that regulate self-renewal and cell fate in these systems are beginning to be elucidated. In addition to pathways such as Wnt, Notch and Hedgehog, known to regulate self-renewal of normal stem cells, tumor suppressor genes such as PTEN (phosphatase and tensin homolog on chromosome 10) and TP53 (tumor protein p53) have also been implicated in the regulation of cancer stem cell self-renewal. In cancer stem cells, these pathways are believed to be deregulated, leading to uncontrolled self-renewal of cancer stem cells which generate tumors that are resistant to conventional therapies. Current cancer therapeutics based on tumor regression may target and kill differentiated tumor cells, which compose the bulk of the tumor, while sparing the rare cancer stem cell population. The cancer stem cell model suggests that the design of new cancer therapeutics may require the targeting and elimination of cancer stem cells. Therefore, it is imperative to design new strategies based upon a better understanding of the signaling pathways that control aspects of self-renewal and survival in cancer stem cells in order to identify novel therapeutic targets in these cells.