This review summarizes current knowledge of the cardiac rapidly activating delayed rectifier potassium current (I(Kr)), and its connection to drug-acquired QT prolongation and the associated risk of ventricular arrhythmia and fibrillation. The molecular characterization of hERG as the structural correlate of I(Kr) and the link between inherited long QT and the KCNH2 gene (hERG), have facilitated mechanistic studies of drug-acquired QT prolongation. The development of high throughput assays to evaluate drug effects on hERG has provided an avenue to determine structure activity relations (SAR) within chemical series. More than 10 years of collective data and structural considerations support the notion that hERG is an unusually promiscuous target among potassium channels, but that defining SAR within a chemical series is a viable strategy to reduce or eliminate hERG activity. Despite a critical need to minimize drug effects on hERG, one should always keep in mind that hERG is not the only structural correlate of QT prolongation, and that QT prolongation is a sub-optimal biomarker for ventricular arrhythmia and fibrillation.