Our laboratory identified CaMKII as an important pro-arrhythmic and pro-cardiomyopathic signal. Our work has provided proof of concept evidence motivating active efforts in biotech and the pharmaceutical industry to develop therapeutic CaMKII inhibitory drugs to treat heart failure and arrhythmias. My group discovered that CaMKII is activated by oxidation and excessive CaMKII activity participates in cellular injury in response to diverse ‘upstream’ signals, including the renin-angiotensin-aldosterone pathway and endotoxin by oxidative activation. CaMKII is multifunctional because it has multiple ‘downstream’ targets. CaMKII catalyzed phosphorylation of diverse proteins in myocardium appears to coordinate activity of many or most voltage-gated ion channels, Ca2+ homeostatic proteins and gene transcription. Under physiological conditions, CaMKII is important for excitation-contraction coupling and fight or flight heart rate increases. However, myocardial CaMKII is excessively activated during disease conditions where it contributes to loss of intracellular Ca2+ homeostasis, membrane hyper-excitability, premature cell death, and hypertrophic and inflammatory transcription. These downstream targets appear to contribute coordinately and decisively to heart failure and arrhythmias. Recently, our group has developed evidence that CaMKII also participates in asthma and diabetes.