The epithelia of the gastrointestinal tract represent one of the most rapidly self-renewing tissues in the adult mammalian body. The tract lining is concurrently exposed to chemical stress and mechanical tensions. Consequently, the combination of high proliferation rate and environmental stress results in the accumulation of somatic mutations hitting tumor suppressor genes or proto-oncogenes. More than 50% of all colorectal tumors harbor inactivating mutations in the adenomatous polyposis coli (APC) gene resulting in the aberrant activation of the Wnt signaling pathway. Intriguingly, under physiological conditions the pathway is required for maintenance of the intestinal epithelia and its blocking diminishes the proliferative capacity of the intestinal stem cells.