In this review, the role of S-nitrosylation (SNO) in cardioprotection will be discussed. This review will cover the methodology used to measure SNO levels, and the mechanisms by which SNO serves to modulate cell function and mediate protection. We will also consider whether SNO acts through many targets or whether there are a few key SNO proteins that mediate protection. Issues regarding the percentage of the total protein which is SNO and how this plays a role in the modulation of cell function will also be discussed. The role of nitric oxide synthase uncoupling in cardioprotection will also be addressed. This article is part of a Special Section entitled “Post-translational Modification.”