Barrett’s esophagus (BE) is defined as the metaplastic conversion of esophageal squamous epithelium to intestinalized columnar epithelium. As a premalignant lesion of esophageal adenocarcinoma (EAC), BE develops as a result of chronic gastroesophageal reflux disease (GERD). Many studies have been conducted to understand the molecular mechanisms of this disease. This review summarizes recent results involving squamous and intestinal transcription factors, signaling pathways, stromal factors, microRNAs, and other factors in the development of BE. A conceptual framework is proposed to guide future studies. We expect elucidation of the molecular mechanisms of BE to help in the development of improved management of GERD, BE, and EAC.