Prostaglandin E₂ (PGE₂) is one of the most typical lipid mediators produced from arachidonic acid (AA) by cyclooxygenase (COX) as the rate-limiting enzyme, and acts on four kinds of receptor subtypes (EP1–EP4) to elicit its diverse actions including pyrexia, pain sensation, and inflammation. Recently, the molecular mechanisms underlying the PGE₂ actions mediated by each EP subtype have been elucidated by studies using mice deficient in each EP subtype as well as several compounds highly selective to each EP subtype, and their findings now enable us to discuss how PGE₂ initiates and exacerbates inflammation at the molecular level. Here, we review the recent advances in PGE₂ receptor research by focusing on the activation of mast cells via the EP3 receptor and the control of helper T cells via the EP2/4 receptor, which are the molecular mechanisms involved in PGE₂-induced inflammation that had been unknown for many years. We also discuss the roles of PGE₂ in acute inflammation and inflammatory disorders, and the usefulness of anti-inflammatory therapies that target EP receptors. This article is part of a Special Issue entitled “Oxygenated metabolism of PUFA: analysis and biological relevance”.