Methadone is used as the pharmacologic mainstay for substitution for illegal opiates and as analgesic for chronic or cancer-related pain. Given the benefits of methadone substitution for illicit opioids, the finding of an association between methadone and prolongation of cardiac depolarization (QT prolongation) and torsades de pointes is of great concern. QT prolongation can occur with many drugs and is a potentially lethal adverse drug reaction, necessitating risk monitoring and therapeutic alternatives in some patients. Recent studies suggest that QT prolongation with methadone is context dependent: occurrence is more frequent with high doses of methadone, concomitant administration of CYP3A4 inhibitors, hypokalemia, hepatic failure, administration of other QT prolonging drugs and pre-existing heart disease. The valued benefit of methadone substitution therapy on the one hand and the increased cardiovascular risk in particular situations on the other illustrate the difficulties in dealing with drug-induced QT prolongation in general.