Understanding all facets of membrane microdomains in normal and cancerous cells within the digestive tract is highly important, not only from a clinical point of view, but also in terms of our basic knowledge of cellular transformation. By studying the normal and cancer stem cell-associated molecule CD133 (prominin-1), novel aspects of the organization and dynamics of polarized epithelial cells have been revealed during the last decade. Its association with particular membrane microdomains is highly relevant in these contexts and might also offer new avenues in diagnosis and/or targeting of cancer stem cells.