Methadone has numerous advantages as an analgesic, which have supported its recent increase in use. However, methadone also has a pharmacological profile as an opioid that differentiates it from other, better known or more widely used opioids. It also has unusual pharmacodynamics, pharmacokinetics, and metabolism that must be considered for safe use of methadone as an analgesic. This review looks at the history of methadone use as an analgesic and its properties that distinguish it as an unusual, and potentially, unstable opioid.