Ranolazine, the first member of a newer class of medications, is a piperazine derivative that was first approved by the US Food and Drug Administration in 2006 as a treatment for chronic angina. In 2008, ranolazine received a new indication for the treatment of chronic angina, allowing for its first-line use. Ranolazine's mechanism of action differs fundamentally from that of currently available anti-ischemic drugs, thus introducing a new paradigm to complement what had been considered conventional therapy. This article outlines this mechanism of action, with a focus on myocardial ischemia and on aspects that may assist in fully exploiting ranolazine's therapeutic potential. Although the mechanism of action initially postulated to be responsible for ranolazine's antianginal effect was inhibition of fatty acid oxidation, current evidence suggests alternative explanations. Chief among them is its role as a selective inhibitor of the late component of the Na1 current. The late sodium current has been shown, in several models, to be at the root of a wide spectrum of electrical, contractile, and metabolic derangements.Thus, ranolazine, in addition to its electrophysiologic role, has an influence on cardiomyocyte metabolism, excitation-contraction coupling, and myocardial perfusion. This explains both its efficacy as an antianginal agent and the spectrum of clinical effects observed in human trials, including electrical stabilization and glycemic effects. Accordingly, this article focuses on the current evidence that supports late sodium current inhibition as a plausible mechanism of ranolazine's therapeutic efficacy.