Normal tissue homeostasis involves a careful balance between the normal cell loss and renewal. Stem and progenitor cells help maintain this precise and fine balance through their ability of self-renewal in a tightly regulated manner. In this regard, the gastrointestinal epithelium is unique in that cell proliferation, differentiation, and apoptosis occur in an orderly fashion along the crypt-villus axis. The colonic crypt is primarily a proliferative compartment, is monoclonal and is maintained by stem cells. The concept of tissue stem cells capable of giving rise to all differentiated cells within a given tissue has led to the concept of a cellular hierarchy in tissues and in tumors including colorectal cancer (CRC). Thus, only a few cells may be necessary and sufficient for tissue repair or tumor regeneration. However, such a proposition also raises questions regarding the precise methods and markers to identify such population and to define the circumstantial evidences and place for the origin and establishment of the early mutant stem-cell population. Thus, it is imperative that we understand what cancer stem cells (CSC) are and their potential association with cancer in a tissue specific manner. In this review, we have summarized the current knowledge of stem cell organization and CSC within the colonic epithelium and discussed the potential role of CSC in the development and/or progression of CRC and as targets for therapeutic interventions.