Human colorectal epithelium is composed mainly of columnar, mucous and endocrine cells; origin of these cell lineages from a multi-potential stem cell at the base of the crypt (the Unitarian hypothesis) has been proposed but not yet demonstrated. Gut endocrine cells have variously been considered of neural crest or endodermal origin, but conclusive evidence, particularly in humans, is lacking. It has been shown that in mouse gastrointestinal tract, a single progenitor cell gives rise to both columnar and mucous cells, but it has yet to be demonstrated that such a progenitor cell can also give rise to endocrine cells. Here, a single human rectal adenocarcinoma cell has been shown to differentiate into columnar, mucous and endocrine cells; therefore all epithelial lineages are of clonal origin. Additionally, these results show that human colorectal enteroendocrine cells, at least in neoplastic epithelium, have an endodermal origin.