Methadone is highly effective in treating opioid dependence, and it is also used as an analgesic for second-line management of chronic pain. However, recent increases in methadone-related deaths have instigated controversy about the use of this medication. In this paper, we evaluate risk factors for methadone mortality in opioid dependent and pain populations and present guidelines for initiating methadone treatment in these two populations to minimize the risk of death. Early research with methadone-maintained patients revealed that methadone fatalities occur primarily due to respiratory arrest during methadone induction and in the context of polysubstance use. Recent reports of methadone deaths emphasize chronic pain populations, methadone-related QTc prolongation, and the possibility of inducing Torsade de pointes (TdP), a potentially fatal ventricular arrhythmia. Retrospective analyses of these deaths show that patients who develop TdP often present with multiple risk factors, including high methadone doses, use of other medications that cause QTc prolongation, and electrolyte abnormalities. To minimize fatalities, guidelines are presented for initiating methadone in opioid treatment and pain populations that consider the drug's pharmacology along with behavioral, medical and psychiatric risk factors.