The purpose of this article is to review the basis of arrhythmogenesis, the functional and clinical role of the late Na current, and its therapeutic inhibition. Under pathological conditions such as ischemia and heart failure this current is abnormally enhanced and influences cellular electrophysiology as a proarrhythmic substrate in myocardial pathology. Ranolazine the only approved late Na current blocker has been demonstrated to produce antiarrhythmic effects in the atria and the ventricle. We summarize recent experimental and clinical studies of ranolazine and other experimental late Na current blockers and discuss the significance of the available data.