The fine-tuning between cell proliferation and differentiation of self-renewing stem cells and pluripotent progenitors in gastric glands and colon epithelial crypts is coordinated by the mechanisms that regulate colon epithelial cell migration and guidance along the crypt axis. This leads to the acquisition of specialized cellular functions and the exfoliation of desquamated senescent and apoptotic epithelial cells at the apical mucosa interface with the gut lumen. Self-renewing stem cells and pluripotent progenitors are involved in the clonal and polyclonal growth of digestive tumors. Several lines of evidence support the existence of a subpopulation of cancer cells with stem cell-like (SCL) phenotypes in solid tumors of breast and digestive system. Consistently, epithelial cancer cell lines in long-term culture are phenotypically and functionally heterogeneous. It is suggested that only a small proportion of transformed cells are clonogenic in vivo and ex vivo to form colonies and to initiate tumor growth in immunodeficient mice. A discrete subpopulation of tumor -initiating SCL cancer cells are highly competent to survive, propagate and spread through the invasive and metastatic cascade. A better understanding of the mechanisms driving the plasticity and pluripotency of stem cells, their derived progenitors and SCL colon cancer initiating cells during tumor progression will open new avenues for the early detection and treatment of local and distant tumors of the digestive tract.