The cardiac sarcolemmal Na⁺/H⁺ exchanger (NHE) is a membrane glycoprotein encoded by the ubiquitously expressed NHE1/SLC9A1 gene, which is one of nine currently known members of the solute carrier 9 (SLC9) gene family. Based largely on experiments with selective pharmacological inhibitors, NHE1 activity has been identified as a causal or permissive factor in the inotropic and growth responses of myocardium to neurohormonal and mechanical stimuli, and in the development of myocardial injury during ischaemia and reperfusion and myocardial hypertrophy and remodeling during haemodynamic overload. Data from recent clinical trials with cariporide, a selective NHE1 inhibitor, support earlier pre-clinical work and indicate an important role for NHE1 activity in myocardial injury during ischaemia and reperfusion in humans. However, serious adverse effects preclude therapeutic application of the treatment modality that was tested. Improved understanding of the molecular signaling mechanisms that regulate NHE1 activity in healthy and diseased myocardium may lead to the development of new approaches to its therapeutic manipulation, in a cardiac- and/or disease-specific manner. Recent studies in isolated myocytes indicate that extracellular signal regulated kinases 1 and 2 (ERK1/2) and their downstream effector, the 90 kDa ribosomal S6 kinase (p90RSK), play key roles in mediating increased sarcolemmal NHE activity in response to diverse stimuli, such as prolonged intracellular acidosis, oxidative stress and stimulation of Gq protein-coupled receptors. Interestingly, recent data suggest that stimulation of some Gi protein-coupled receptors (e.g. adenosine A1 receptors) inhibit the increase in sarcolemmal NHE activity that arises from stimulation of Gq protein-coupled receptors, such as α1-adrenoceptors. It appears that the dynamic regulation of NHE1 kinase and phosphatase activities and localization underlies much of the acute receptor-mediated regulation of sarcolemmal NHE activity, and investigations are ongoing to determine the molecular mechanism(s), including the critical phosphorylation sites, that are responsible. Future therapeutic approaches may target attenuation of increased myocardial NHE1 activity in response to pathological stimuli, rather than the global inhibition of ion transport by this ubiquitously expressed protein.