Without the ion selectivity of voltage-gated ion channels, excitable cells could not generate more than a few millivolts of resting potential, much less produce action potentials. Even when the loss of selectivity occurs in just one type of K+ channel in the heart, the outcome may be catastrophic, suggests a report in this issue of Circulation Research .1 A defect in K+ selectivity caused by a mutation near the “signature sequence” in the pore of HERG channel subunits may contribute as a new mechanism to the prolongation of the action potential and the associated susceptibility to life-threatening torsades de pointes arrhythmias. Since chromosome 7-linked long-QT syndrome (LQT2) was first mapped to HERG ,2 a relative of the Drosophila and mammalian eag genes,3 we have learned much about the pathology of the disease and the underlying physiological mechanisms that have gone awry. In heterologous expression systems, the subunits encoded by the wild-type HERG gene assemble to form channels with the functional properties of I Kr,4 5 an unusual repolarizing current first identified by its sensitivity to the antiarrhythmic agent E-4031.6 Our understanding of how I Kr participates in repolarization has emerged largely from voltage-clamp analyses of the remarkable tail currents dominating the HERG current profile. At the positive voltages typically reached at the peak …