Prostaglandin E2 (PGE2) is one of the most important biologically active prostanoids which exerts its actions mainly by binding to four distinct E-type prostanoid receptors: EP1, EP2, EP3, and EP4. These four G protein-coupled receptors (GPCRs) exhibit differences in signal transduction mechanisms, tissue localization, and regulation of expression. EP2 receptors are expressed in many tissues and cells to mediate various PGE2 actions. The receptors couple to Gs to stimulate the cAMP second messenger signal transduction pathway. EP2 receptors play important roles in mucosal protection, gastrointestinal secretion, and motility. The diverse effects of PGE2 acting via EP2 receptors make it an interesting drug target. Therefore, EP2 subtype selective agonists, antagonists, and modulators have been identified with potential therapeutic applications.