Methadone is increasingly prescribed for chronic pain, yet the associated mortality appears to be rising disproportionately relative to other opioid analgesics. We review the available evidence on methadone-associated mortality, and explore potential pharmacokinetic and pharmacodynamic explanations for its greater apparent lethality. While methadone shares properties of central nervous system and respiratory depression with other opioids, methadone is unique as a potent blocker of the delayed rectifier potassium ion channel (IKr). This results in QT-prolongation and torsade de pointes (TdP) in susceptible individuals. In some individuals with low serum protein binding of methadone, the extent of blockade is roughly comparable to that of sotalol, a potent QT-prolonging drug. Predicting an individual's propensity for methadone-induced TdP is difficult at present given the inherent limitations of the QT interval as a risk-stratifier combined with the multifactorial nature of the arrhythmia. Consensus recommendations have recently been published to mitigate the risk of TdP until further studies better define the arrhythmia risk factors for methadone. Studies are needed to provide insights into the clinical covariates most likely to result in methadone-associated arrhythmia and to assess the feasibility of current risk mitigation strategies.