Human ether-a-go-go-related gene (HERG) subunits mediate a K+ current that is required for normal repolarization of the cardiac action potential. The unintentional inhibition of HERG currents by numerous medications results in prolongation of the QT interval, as measured on the electrocardiogram, and is associated with increased risk of patients suffering from life-threatening cardiac arrhythmias. QT interval prolongation is considered a major safety concern by worldwide drug regulatory bodies, and early detection of new compounds with this undesirable side effect has become an important objective for pharmaceutical companies. New studies are shedding light on the structural basis of drug binding and the gating-dependent repositioning of key residues in the inner cavity of HERG, which are responsible for the unusual sensitivity of HERG to pharmacological agents. Insights from these studies may help develop novel strategies to reduce the proarrhythmic potential of the next generation of drugs.