The Na+ channel agonists DPI 201-106, BDF 9148 and BDF 9198 are a new group of positive inotropic agents which increase cardiac contractility in a cAMP independent manner. The most likely mechanism by which positive inotropy is mediated is an enhancement of Na+/Ca2+ exchange activity in response to a Na+ channel agonist induced increase in the cardiac myocyte intracellular Na+ concentration. While the positive inotropic effect of drugs which exert their effects in a cAMP dependent manner is blunted in failing compared to nonfailing myocardium, the efficacy and potency of Na+ channel agonists is not only maintained, but enhanced in failing myocardium. This finding makes these substances interesting for the treatment of patients with heart failure. The positive inotropic effects of the Na+ channel agonists, however, are accompanied by a potential increase in the incidence of cardiac arrhythmias. These side effects might limit the clinical use of Na+ channel agonists and demand future development of Na+ channel modulators without significant arrhythmogenic effects.