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Proarrhythmias due to drug-induced QT prolongation are the second most common cause for drug withdrawal and have caused increasing concern. Two new International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines were recently endorsed in which nonclinical (S7B) and clinical (E14) methodologies are discussed and guidance is given to the industry. This commentary describes the key components of the E14 document, the impact of nonclinical testing on the clinical program, the thorough QT study, and the impact of its result on late-stage development. The studies described in S7B and E14 will contribute to a better understanding of the link between nonclinical assays and QT prolongation in humans. Differences in interpretation among individual regulators in the major regions with respect to measures proposed in the E14 guideline might impact regional regulatory decisions. These differences include the value of nonclinical assays for the subsequent clinical testing and how predictive a negative thorough QT study result is for proarrhythmic risk in patients.