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 the δB or δC 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. Our recent data indicate that the post‐translational modification status of CaMKIIδB/δC variants may have an important influence on reperfusion outcomes. We provided the first evidence that the specific type of CaMKII post‐translational modification has a role in determining target selectivity of downstream Ca2+ transporters. We were also able to demonstrate that the phosphorylated form of CaMKII closely co‐localises with CaMKIIδB in the nuclear/myofilament fraction, contrasting with a co‐enrichment of oxidized CaMKII in the membrane fraction with CaMKIIδC. We have also been able 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 CaMKIIδ may not be an efficacious approach to developing optimal pharmacological interventions for the vulnerable heart. This article is protected by copyright. All rights reserved.