Cardiac arrhythmias are a major epidemiological and public health problem and contribute significantly to sudden cardiac death, heart failure, stroke, suffering, debilitation, and healthcare expenses. In the United States alone, sudden cardiac death is estimated to kill 250 000 to 400 000 people annually. 1 Most sudden death is due to cardiac arrhythmias, 2 with ventricular tachycardia and fibrillation as the most commonly (80%) recorded rhythms in out-ofhospital cardiac arrests. 3 In patients with structural heart disease, mostly resulting from a history of myocardial infarction, arrhythmias are the main cause of death. 4 Atrial fibrillation (AF) and sinus node dysfunction (SND) are the most common sustained arrhythmias. AF affects 2.3 million patients in the United States, 5 and because the prevalence of AF increases with age, it is predicted to increase by 2.5-fold by 2050. 6 Patients with AF have approximately twice the mortality rate of patients in sinus rhythm, 6 and the incidence of stroke is increased by 2-to 7-fold. 7 AF is a costly disease and causes a public health burden estimated at $6.0 to $26.0 billion annually in the United States. 8 SND is associated with increased sudden cardiac death, particularly in patients with heart failure, and a large portion (40%) of mortality in hospitalized patients with heart failure may be secondary to SND. 9 SND is the indication for 60% of the 180000 pacemakers implanted in the United States each year, a procedure that in 2004 accounted for $2 billion in expenses. 10, 11 The negative impact of arrhythmias on human health and medical economics is a major motivating factor for establishing new and effective therapeutic approaches. Cardiac arrhythmias are the result of cell membrane hyperexcitability (the cause of automatic and triggered tachyarrhythmias), defective impulse formation (the cause of SND), or reduction in normal cell-to-cell electric coupling (the cause of conduction system “block” and a component of the zone of slow conduction in most arrhythmias supported by a reentrant circuit). Ion channels, macromolecular protein complexes with a cell membrane–spanning conductance pathway, are the fundamental units of membrane excitability, and rare congenital defects in ion channels or proarrhythmic off-target actions of many drugs can be sufficient to promote arrhythmia risk. However, most arrhythmias are not attributable to monogenic defects or drugs and occur in the biological context of various proarrhythmic factors such as advanced age, increased oxidant stress, ischemia, tissue injury, inflammation, and systemic disease (eg, hypertension, diabetes, heart failure). These proarrhythmic factors appear to favor structural remodeling of cardiac tissue and to predispose certain ion channels to initiate or sustain arrhythmias. Unfortunately, ion channel antagonist drugs have not proved to be broadly applicable, safe, or effective antiarrhythmic agents. 12, 13 Thus, a major goal for science and industry is to define molecular pathways and mechanisms that cause common and life-threatening arrhythmias to develop new and improved therapies. The multifunctional Ca2/calmodulindependent protein kinase II (CaMKII) has emerged as a highly validated molecular mechanism with the potential to connect “upstream” proarrhythmic factors such as oxidation with “downstream” responses such as ion channel hyperactivity, defective intracellular Ca2 homeostasis, tissue damage, and scar formation that promote arrhythmias. Here, we review modern concepts of CaMKII molecular physiology in the context of fundamental arrhythmia mechanisms and consider evidence that CaMKII inhibition could be a broadspectrum …