From the perspective of risk for cardiac arrhythmias and sudden death, the existence of reserve when the cardiac system is stressed is of utmost importance. The large density of sodium channels in cardiac cell membranes ensures that action potential depolarization is achieved with a large margin of safety. Similarly, it is important to ensure availability of sufficient repolarizing current for normal repolarization under various conditions. Reduction of repolarizing current can occur as a result of mutations in ion channels that carry outward current, particularly the fast and slow delayed potassium currents I_Kr and I_Ks. Such hereditary abnormalities can lead to the congenital long QT syndrome (LQT) that is associated with life-threatening arrhythmias and sudden death. Although the congenital form of LQT is relatively rare, the acquired form that is precipitated by drugs that prolong the QT interval is much more common. Many drugs that prolong the QT interval have been associated with ventricular arrhythmias and withdrawn from the market. Most of these drugs have a blocking effect on I_Kr. The concept of “repolarization reserve” requires the availability of sufficient repolarizing current to compensate for such a reduction in I_Kr. We demonstrate that I_Ks can provide the necessary reserve when I_Kr is compromised. This capability of I_Ks results from its kinetic properties (that require interaction between the α- and β-subunits of the channel) that allow channels to accumulate in closed states that are near to the open state and are ready to open “on demand.” Thus, there is a buildup of an available reserve within the channel itself that provides current late during the action potential, when it most effectively influences repolarization. It is possible that reduced capacity to do so (eg, because of I_Ks polymorphisms) renders certain individuals at high risk for drug-induced arrhythmias.