Cardiac arrhythmias occur in a wide variety of conditions where increased intracellular Ca2+ is known to occur, including myocardial ischemia, cardiac glycoside toxicity, congestive heart failure, and excessive prolongation of action potential duration. The multifunctional Ca2+/calmodulin dependent protein kinaseⅡ(CaM kinase) is an important physiologic target for intracellular Ca2+ and regulates key control points for intracellular Ca2+ homeostasis, including L-type Ca2+ current, release and uptake of Ca2+ from the sarcoplasmic reticulum. Since CaM kinase is uniquely positioned to affect Ca2+ sensitive ionic currents and resultant arrhythmias, CaM kinase may also be an effective antiarrhythmic drug target. The transient inward current (Iti) triggers delayed afterdepolarizations, which are a likely cause of Ca2+ overload arrhythmias. The identity of Iti is controversial, but appears to result from different ionic currents depending on the experimental conditions. These currents are likely activated by intracellular Ca2+ because Iti always follows excessive intracellular Ca2+ concentrations (［Ca2+］i). The studies from our laboratory indicate that three different ［Ca2+］i sensitive currents, which could contribute to Iti, are present in rabbit ventricular myocytes. These currents are the Na+/Ca2+ exchanger, the Ca2+ activated Cl- current, and the Ca2+ activated non-selective cation current. We also found that Iti was suppressed by CaM kinase inhibitory peptides in the presence of physiologic solutions. These data support the hypothesis: CaM kinase can augment Iti during clinically relevant conditions, which are associated with increased ［Ca2+］i, and thus act as a proarrhythmic signaling molecule.