Barrett’s esophagus is the condition in which metaplastic columnar epithelium that predisposes to cancer development replaces stratified squamous epithelium in the distal esophagus. Potential sources for the cell or tissue of origin for metaplastic Barrett’s epithelium are reviewed including native esophageal differentiated squamous cells, progenitor cells native to the esophagus located within the squamous epithelium or in the submucosal glands or ducts, circulating bone marrow-derived stem cells, and columnar progenitor cells from the squamocolumnar junction or the gastric cardia that proximally shift into the esophagus to fill voids left by damaged squamous epithelium. Wherever its source the original cell must undergo molecular reprogramming (i.e., either transdifferentiation or transcommitment) to give rise to specialized intestinal metaplasia. Transcription factors that specify squamous, columnar, intestinal, and mucus-secreting epithelial differentiation are discussed. An improved understanding of how esophageal columnar metaplasia forms could lead to development of effective treatment or prevention strategies for Barrett’s esophagus. It could also more broadly inform upon normal tissue development and differentiation, wound healing, and stem cell biology.