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The various biological functions governed by PGE<jats:sub>2<\/jats:sub>are mediated through its four distinct prostaglandin E receptors (EPs), designated as EP1, EP2, EP3, and EP4, among which the EP4 receptor is the one most widely distributed in the heart. The availability of global or cardiac-specific EP4 knockout mice and the development of selective EP4 agonists\/antagonists have provided substantial evidence to support the role of EP4 receptor in the heart. However, like any good drama, activation of PGE<jats:sub>2<\/jats:sub>-EP4 signaling exerts both protective and detrimental effects in the ischemic heart disease. Thus, the primary object of this review is to provide a comprehensive overview of the current progress of the PGE<jats:sub>2<\/jats:sub>-EP4 signaling in ischemic heart diseases, including cardiac hypertrophy and myocardial ischemia\/reperfusion injury. 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