CaMKII regulates many processes in cardiac myocytes. We used FRET-based sensors to measure dynamic beat-to-beat changes in [Ca-CaM] in intact myocytes and mathematical models of CaMKII activation in different cellular domains. CaMKII has acute effects on numerous cardiac ion channels (e.g. Ca, Na, K and ryanodine receptor, RyR) and CaMKII expression and activity is enhanced in heart failure (HF). How do CaMKII effects integrate at the myocyte level to influence cardiac action potential (AP) and arrhythmias? CaMKII-dependent effects on Na current phenocopies a human mutation that causes combined LQT and Brugada syndrome in patients. CaMKII also mediates Ca current facilitation, and these INa &ICa effects tend to prolong AP duration. CaMKII also alters both fast and slow Ito, in ways that shorten APD. The net effect of CaMKII would be to shorten epicardial APD and prolong endocardial APD, which increases transmural dispersion of repolarization, an effect known to be pro-arrhythmic. CaMKII also activates RyR, Ca sparks and waves, and these can increase the propensity for spontaneous diastolic SR Ca release, DADs and triggered arrhythmias. These CaMKII effects on cardiac Ca and K channels may constitute a new acquired post-translational form of arrhythmias in HF patients in whom there is no intrinsic channel defect. These downstream effects of CaMKII on ion channels can also feedback on the Ca handling properties of the myocyte and contribute to altered E-C coupling and contractile function. Thus, altered Ca and Na handling are important in contractile function and arrhythmogenesis in HF.