Protein quality control has been shown to protect the heart from acute stresses such as ischemia and reperfusion (I/R). This dissertation explores two mechanisms by which protein quality control protects the heart from I/R-induced damage. The first study characterizes protein disulfide isomerase-associated 6 (PDIA6) as an endoplasmic reticulum (ER) stress response gene and its ability to protect cultured cardiac myocytes from I/R damage. The second study elucidates the role of alpha-B crystallin (_BC) in protecting the myocardium from I/R injury using a novel knock-out (KO) mouse model. I/R can impair ER protein folding and initiate the ER stress response. ER stress and I/R activate the transcription factor, activating transcription factor 6 (ATF6), which induces numerous genes, many of which have not been examined in the heart. In this study, we presented that, ATF6 induced the PDIA6 gene, which encodes an ER enzyme that catalyzes protein disulfide bond formation. Gain- and loss-of-function studies showed that PDIA6 protected cardiac myocytes against simulated I/R-induced death in a manner that was dependent on the catalytic activity of PDIA6. Thus, by facilitating disulfide bond formation, and enhancing ER protein folding, PDIA6 may contribute to the protective effects of ATF6 in the ischemic heart. Overexpression studies have shown that the small heat shock proteins (sHSP) can protect from I/R damage. Previous studies have shown that hearts harboring the deletion of both _BC and HSPB2, both sHSP family members, were more susceptible to I/R damage. In this study, we generated and characterized a mouse line in which only _BC was deleted _BC KO), in order to clarify the roles of _BC and HSPB2 in cardioprotection. Cardiac morphology and function of the _BC KO mice were indistinguishable from age-matched wild-type (WT) mice, although a few markers of cardiac pathology were elevated, suggesting an underlying phenotype. The function of isolated perfused hearts from _BC KO mice were initially indistinguishable from those from WT mice, however, after I/R, _BC KO mouse hearts exhibited a 50% reduced functional recovery when compared to WT mouse hearts. Thus, _BC is required for maximal functional recovery from I/R-induced injury.