Apelin is the endogenous ligand for the APJ, a member of the G protein coupled receptors family. Apelin/APJ system is widely distributed in central nervous system and peripheral tissues, especially in heart, lung and kidney. Apelin plays important physiological and pathological roles in cardiovascular system, immune system, neuroprotection, etc. This article outlines the protective effect of apelin on ischemia/reperfusion (I/R) injury. Apelin could activate multiple protective mechanisms to prevent heart, brain, liver and kidney I/R injury. Apelin/APJ system may be a promising therapeutic target for ischemic and other related diseases.