For the past half century, oncologists have had systemic drugs available, agents that are able to induce tumor responses in patients with colorectal cancer. However, in cases of advanced colorectal cancer, these regimens are almost never curative. The recently introduced concept that cancer stem cells (SCs) drive tumor growth suggests a reason for these therapeutic failures--current chemotherapeutics target rapidly dividing cells but cancer SCs divide only slowly, and, they are relatively resistant to cytotoxic systemic therapies. It also suggests a solution--development of therapeutics that target cancer SCs. However, there is a paucity of information about the mechanisms by which SC populations are maintained and about the mechanisms by which tumor SCs are involved in colon cancer development. In this article, we discuss these mechanisms and recent developments in the identification and isolation of colon cancer SCs using new SC markers. We then discuss the role of SCs in homeostasis of normal colonic epithelium, and mechanisms by which dysregulation of crypt mechanisms can lead to initiation and progression of colon cancer. Our hypothesis, which has received recent experimental support, is that the mechanism that links abnormalities at the gene level (eg, APC mutations) and abnormalities at the tissue level (eg, proliferative shift, dysplasia, carcinoma) from cancer initiation to metastasis is SC overpopulation. Finally, we discuss the concept that symmetric cancer SC division is an essential mechanism that drives tumor growth, and that development of a new generation of therapeutics that target colon cancer SCs by inhibiting symmetric SC division holds promise for truly curative approaches for patients with advanced colorectal cancers.