We have identified Lgr5 as a facultative component of the Wnt receptor complex specifically expressed on cycling stem cells in the intestine, colon, stomach, hair-follicles, ovary and embryonic kidney. Using a 3D ex vivo culture system, freshly isolated Lgr5+ stem cells spontaneously generate self-organizing, self-renewing epithelial “organoids”, providing a physiological, renewable source of patient epithelia for both research and clinical applications. Employing in vivo clonal fate mapping strategies in the stomach, we further show that a balanced homeostasis of the glandular epithelium and stem cell pools is achieved via neutral competition between symmetrically dividing Lgr5+ stem cells. Long-term ablation of the Lgr5+ cell compartment in vivo severely impairs epithelial homeostasis in both the pyloric antrum and the corpus, establishing the Lgr5+ stem cell pool as being critical for daily maintenance of the gastric mucosa. We additionally characterize the transcriptomes Lgr5+ stem cells in mouse intestine, colon and stomach, revealing new gastric stem cell-specific markers that can be used to isolate human gastric stem cells for regenerative medicine applications and for use in selectively targeting cancer-causing mutations to the Lgr5+ stem cell compartment in mice as a means of evaluating their contribution to gastric cancer initiation and progression.