Methadone is a unique mu opioid agonist, which also has delta receptor affinity and properties of N-methyl-D-aspartate receptor antagonism and monoamine reuptake inhibition. It is mainly used in the setting of uncontrolled pain or dose-limiting toxicity. Caution is advised when switching to methadone, especially from high doses of previous opioid, due to its variable conversion ratio and the potential for delayed toxicity due to its long half-life. Increasing evidence of risk also exists for a prolonged QT interval and torsades de pointes with very large doses of methadone. Methadone is likely safer when used at lower doses as a first-line opioid, but its potential as such has not received enough formal evaluation. Randomized controlled trials are needed to assess the effectiveness and safety of methadone compared with other opioids and to further evaluate its role in the treatment of neuropathic pain.