The Na(+)/Ca(2+) exchanger (NCX) is the main Ca(2+) extrusion mechanism of the cardiac myocyte and thus is crucial for maintaining Ca(2+) homeostasis. It is involved in the regulation of several parameters of cardiac excitation contraction coupling, such as cytosolic Ca(2+) concentration, repolarization and contractility. Increased NCX activity has been identified as a mechanism promoting heart failure, cardiac ischemia and arrhythmia. Transgenic mice as well as pharmacological interventions have been used to support the idea of using NCX inhibition as a future pharmacological strategy to treat cardiovascular disease.