The article by Galizia et al1 is an intriguing, well-designed, and timely study that lends credence to the controversial concept of colorectal cancer stem cells (CSCs). In recent years, the traditional model of colorectal carcinogenesis is being challenged by the CSC model. In the traditional clonal model of carcinogenesis, each differentiated cell in a cancer has the potential to form a cancer, whereas the CSC model holds that only the long-lived stem cells have the potential to accumulate all the needed mutations. Cancer stem cells are characterized by self-renewal and pluripotency whereby each CSC can differentiate into mature and diverse cancer cells, which are then capable of tumor initiation, growth, invasion, and metastasis.2- 4 This paradigm shift has obvious clinical connotations because CSC may also account for the failure of current chemotherapeutic regimens to cure metastatic colorectal cancers. Conventional cytotoxic chemotherapy targets only rapidly dividing cells, while the slowly proliferating CSCs may escape cell death, resulting in eventual cancer recurrence and metastasis. These CSCs are also enriched with multidrug-resistant proteins that may allow them to survive. On the bright side, a better understanding of CSCs will allow us to target these subpopulations and potentially eradicate tumors. The evidence for the CSC model is strongest in acute myeloid leukemias,3,4 but results of recent studies3 in brain, breast, and colorectal cancers have been promising. However, there is widespread controversy within the cancer field because the marks that identify these CSCs keep evolving and because most investigators have used mouse xenograft models rather than primary human models.