Extensive pre-clinical work indicates that inhibition of the Na(+)/H(+) exchanger (NHE) affords significant protection to myocardium subjected to ischaemia and reperfusion. By contrast, clinical studies with the NHE inhibitors cariporide, eniporide and zoniporide, in patients with evolving myocardial infarction and those at risk of myocardial infarction, have provided largely disappointing data. Nevertheless, some of these studies have confirmed that, in certain settings, NHE inhibition does indeed protect human myocardium. Furthermore, pre-clinical work suggests that NHE inhibition may provide therapeutic benefit in heart failure also. As an alternative to direct and global NHE inhibition, which may trigger non-cardiac adverse effects, the molecular mechanisms that stimulate cardiac NHE activity in disease may be targeted to attenuate such activity selectively in jeopardized tissue. Many factors associated with cardiac pathology activate RSK, an established NHE kinase, and several selective RSK inhibitors have been described recently. The role of RSK as a potential therapeutic target for indirectly suppressing cardiac NHE activity warrants further investigation.