Studies to identify the cells that fuel colorectal cancer (CRC) cell renewal and metastasis have shown that such behavior is enriched in a subpopulation of cells with stem cell-like features or tumor-initiating cells. The identification of drugs that target tumor-initiating cells in CRC will provide unique, new therapeutic opportunities. Two publications in this issue of Gastroenterology now demonstrate an important role for c-Kit signaling, a receptor tyrosine kinase that can be targeted with the clinically approved inhibitor imatinib, in the growth and maintenance of tumor-initiating cells in CRC.