Control of cardiomyocyte cytosolic Ca2+ levels is crucial in determining inotropic status and ischemia/reperfusion stress response. Responsive to fluctuations in cellular Ca2+, Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase integral to the processes regulating cardiomyocyte Ca2+ channels/transporters. CaMKII is primarily expressed either in theδB orδC splice variant forms, which may mediate differential influences on cardiomyocyte function and pathological response mechanisms. Increases in myocyte Ca2+ levels promote the binding of a Ca2+/calmodulin complex to CaMKII, to activate the kinase. Activity is also maintained through a series of post-translational modifications within a critical region of the regulatory domain of the protein. Recent data indicate that the post-translational modification status of CaMKIIδB/δC variants may have an important influence on reperfusion outcomes. This study provided the first evidence that the specific type of CaMKII post-translational modification has a role in determining target selectivity of downstream Ca2+ transporters. The study was also able to demonstrate that the phosphorylated form of CaMKII closely co-localizes with CaMKIIδB in the nuclear/myofilament fraction, contrasting with a co-enrichment of oxidized CaMKII in the membrane fraction with CaMKIIδC. It has also been possible to conclude that a hyper-phosphorylation of CaMKII (Thr287) in reperfused hearts represents a hyper-activation of the CaMKIIδB, which exerts anti-arrhythmic actions through an enhanced capacity to selectively increase sarcoplasmic reticulum Ca2+ uptake and maintain cytosolic Ca2+ levels. This suggests that suppression of global CaMKIIδmay not be an efficacious approach to developing optimal pharmacological interventions for the vulnerable heart.