Anticancer therapy relies on targeting highly proliferative cells. Commonly used chemotherapy does not selectively target individual cancer cells. The identification of distinct cancer stem cells that have the unique ability to engraft tumors and maintain cancer self-renewal may prove vital in the development of novel and selective anticancer therapy. Therefore, the discovery of colorectal cancer stem cell markers has attracted much attention. However, it is still controversial whether current markers for cancer cell subpopulations are selectively labeling cancer stem cells, whether these markers contribute to cancer stem cell function and how many cells within tumors maintain this stemness. For this reason, novel anticancer drug approaches need to be considered, that target selective cell death pathways, the tissue microenvironment and, additionally, multiple specific cancer (stem) cell markers. This triple approach of anticancer therapy may contribute to novel chemotherapeutic strategies and improve the understanding of human intestinal tumorigenesis; in particular, the distinct contribution of human cancer stem cells.