Nitric oxide (NO) is a potent mediator of blood vessel dilation and is released by several cell sources. Red blood cells (rbc) release NO when hemoglobin that has been S-nitrosylated at Cys93 of the β-chain (βCys93) transitions from the oxygenated form to the deoxygenated form. This transition occurs in response to reduced tissue oxygenation and is an important physiologic regulator of hypoxic vasodilation. In this issue of the JCI, Zhang and colleagues demonstrate that S-nitrosylation of hemoglobin at βCys93 is important for tissue oxygenation after cardiac injury. Mice harboring mutations that prevent S-nitrosylation of βCys93 had higher rates of morbidity and mortality following cardiac injury compared with WT; however, adaptive cardiac vascularization was increased in some mutant mice and reduced cardiac injury in these animals. The results of this study reveal a previously unexplored role of S-nitrosylated hemoglobin in cardioprotection.