Background　Na+/H+ exchanger（NHE） is a membrane protein， and responsible for maintaining normal intracellular pH and cell volume. Activation of NHE after ischemia subsequently causes cerebral ischemic damage via Na+ - and Ca2+-mediated toxic effects. NHE-1 is the most abundant isoform in central nervous system. Highly selective NHE-1 inhibitor HOE-642 can decrease the intracellular Na+， Ca2+ overload， mitochondria Ca2+ overload， cell death， suppress microglial activation and proinflammatory responses. In addition， improved functional outcome also follows administration of HOE-642.　Objective　To review the neuroprotective mechanisms of HOE-642 on cerebral ischemic injury.　Content　This article reviews the structure， function， tissue distribution of NHE， and the neuroprotective mechanisms of HOE-642 on cerebral ischemic injury.　Trend　With the in-depth study of cerebral ischemic injury， the neuroprotective mechanisms of HOE-642 will continue to be updated， especially for the effects of the mitochondrial permeability transition pore （mPTP）.