Clinically, methadone is most known for its use in the treatment of opioid maintenance therapy. However, methadone's pharmacological profile makes it an excellent analgesic that can enhance acute and chronic pain management. It is a potent μ-receptor agonist with a longer elimination half-life than most clinically used opioids. In addition, methadone inhibits serotonin and norepinephrine uptake, and it is an N-methyl-D-aspartate antagonist. These distinct analgesic pathways mediate hyperalgesic, allodynic, and neuropathic pain. Its unique analgesic properties provide several essential benefits in perioperative use, neuropathic pain, cancer, and noncancer pain. Despite these proven clinical utilities, methadone has not been used widely to treat acute and chronic pain in opioid naïve patients. This article describes the unique pharmacology of methadone and provides emerging evidence to support its application in acute and chronic pain management. Pain management options and guidelines for surgical patients on methadone are discussed as well.