Many questions remain unanswered regarding the pathogenesis and the cell origin of Barrett's esophagus. Recent studies suggest that progenitor cell populations, which are presumed to reside at the basal layer in the squamous epithelium and at the esophageal glands duct epithelium, may differentiate into a glandular phenotype leading to the development of columnar epithelium in the distal esophagus. Other studies also support the hypothesis that cardiac epithelium may precede the occurrence of specialized intestinal metaplasia. It remains unclear whether cardiac-type epithelium in Barrett's esophagus arises from squamous epithelium or from migration of native cardiac epithelium at the EGJ into the distal esophagus. Experimental animal models of chronic reflux esophagitis, although with some shortcomings when researchers extrapolate the study data to the human situation, have provided interesting insights into possible mechanisms associated with the occurrence of Barrett's esophagus. A better understanding of the molecular mechanisms regulating the development of Barrett's esophagus is necessary for developing new strategies directed toward prevention and treatment of this metaplastic condition with a potential risk for malignant transformation.