The Ca²⁺-independent transient outward K⁺ current (I_to) plays a critical role in underlying phase 1 of repolarization of the cardiac action potential and, as a result, is central to modulating excitation-contraction coupling and propensity for arrhythmia. Additionally, I_to and its molecular constituents are consistently reduced in cardiac hypertrophy and heart failure. In this review, we discuss the physiological role of I_to as well as the molecular basis of this current in human and canine hearts, in which I_to has been thoroughly studied. In particular, we discuss the role of I_to in the action potential and the mechanisms by which I_to modulates excitation-contraction coupling. We also describe the effects of mutations in the subunits constituting the I_to channel as well as the role of I_to in the failing myocardium. Finally, we review pharmacological modulation of I_to and discuss the evidence supporting the hypothesis that restoration of I_to in the setting of heart failure may be therapeutically beneficial by enhancing excitation-contraction coupling and cardiac function.