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A wide array of drugs can cause marked QT prolongation with the associated risk of torsade de pointes. The large number of drugs with this potential, the correspondingly large number of patients exposed to such drugs, and the potentially fatal outcome make drug-induced long QT syndrome an important public health problem. This review focuses on mechanisms underlying QT prolongation and proarrhythmia, risk factors, including the role of genetic variants, and the unifying framework of reduced repolarization reserve.While most drugs that prolong the QT block a specific potassium channel, novel mechanisms altering protein trafficking have been discovered. The progression to torsade de pointes may be less related to degree of QT prolongation than to drug effects on transmural dispersion or variability of repolarization. Our understanding of certain predisposing risk factors has been further refined.Ongoing research continues to elucidate the mechanisms underlying drug-induced long QT syndrome. Importantly, studies are establishing improved predictors of risk for progression to torsade de pointes, in addition to the degree of QT prolongation, which is an imperfect predictor. Nonetheless, drug-induced long QT syndrome and torsade de pointes pose unique challenges for clinicians, researchers, drug-development programs, and regulatory agencies.