Barrett’s esophagus is an intestinal metaplasia in patients with chronic acid reflux and the dominant risk factor for esophageal adenocarcinoma.  This metaplasia is irreversible and proving to be resistant to physical methods of elimination such as radiofrequency ablation.  While generally assumed to arise from the transcommitment of esophageal squamous stem cells, our mouse models that lose esophageal stem cells show a robust formation of Barrett’s in a matter of days.  We traced the origins of this Barrett’s metaplasia to a discrete group of residual embryonic cells that reside at the squamocolumnar junction in all individuals that expands in an opportunistic fashion during damage to the esophageal cells.  Given the apparent high rates of recurrence of Barrett’s following RFA, presumably due to the failure to eradicate every stem cell in Barrett’s glands, we set out to develop strategies focused on targeted elimination of these stem cells.  Early results indicated that we have cloned Barrett’s as well as esophageal and gastric stem cells, and that their comparative expression profiles reveal cell surface antigens and discrete pathways for selective therapeutic intervention.