There is growing awareness of the extent to which sex and sex steroids can influence both cardiac function and the outcomes of cardiac stress exposure, including cardiac ischemia. However, information is lacking about the basic mechanisms responsible for these sex differences. Estrogen production is dependent on androgen availability and linked through the enzymatic actions of aromatase, which we have recently shown to be expressed locally in the heart. Cardiomyocytes express estrogen and androgen receptors and are functionally responsive to fluctuations in sex steroid levels. Previous experimental studies have reported fundamental differences between male and females in excitation-contraction coupling and cardiomyocyte Ca²⁺ handling processes. Indeed, our evidence suggests female myocytes operate at a relatively low Ca²⁺ cycling load (vs males) – with endogenous estrogen and testosterone playing reciprocal regulatory roles in maintaining this difference. Ca²⁺ is a major causative factor in many of the pathologies associated with ischemia/reperfusion, including arrhythmogenesis, contractile dysfunction and cardiomyocyte death. Recent interest has focused on the actions of Ca²⁺/calmodulin-dependent kinase II (CaMKII) – a serine/threonine kinase responsive to alterations in cellular Ca²⁺ levels that phosphorylates and functionally modulates many of the ion channels/transporters centrally involved in excitation-contraction coupling. Inhibiting CaMKII in ischemia reduces Ca²⁺ overload, myocardial infarction, and incidence of ventricular arrhythmias. However, this work has almost exclusively been performed in males only and the sex-specificity of CaMKII actions remains undefined. We have very recently shown that, in accordance with lower Ca²⁺ cycling load, CaMKII activity is lower in basal female hearts (vs male). Surprisingly though, upregulation of CaMKII in early reperfusion is actually accentuated in female hearts (vs male), despite lower arrhythmia incidence.  These findings suggest the relationship between CaMKII activation and arrhythmogenesis in females is distinctive, and that the actions of CaMKII are more complex than previously described. Further studies will discern how CaMKII actions are determined by Ca²⁺ and oxidative stress conditions, and how this may be modulated in complex disease settings (cardiac hypertrophy, diabetes).