Methadone oral tablets initially became available on the Japanese market in MAR－2013. Methadone, which has different pharmacological properties from other opioids including morphine, can cause serious adverse drug reactions such as respiratory depression and QT prolongation. One of the causes of these reactions is its extremely complex pharmacokinetics. Methadone is mostly metabolized in the liver, with a variety of metabolic enzymes, including cytochrome P450 (CYP) 3A4, CYP2B6, and CYP2D6, being involved. The characteristics of methadone include self-induction of metabolism, delayed excretion due to alkaline urine, and an extremely long half-life requiring a long time to achieve a steady state. Without a full understanding of its complex pharmacokinetics, the blood concentration of methadone is not maintained at a constant level, and serious adverse events could happen due to an unexpected increase in its blood concentration. Herein, for safe clinical use by physicians and pharmacists, we summarize the pharmacokinetics of methadone.