Alpha2 agonists have been in clinical use for decades, primarily in the treatment of hypertension. In recent years, alpha2 agonists have found wider application, particularly in the fields of anesthesia and pain management. It has been noted that these agents can enhance analgesia provided by traditional analgesics, such as opiates, and may result in opiate-sparing effects. This has important implications for the management of acute postoperative pain and chronic pain states, including disorders involving spasticity or myofascial pain, neuropathic pain, and chronic daily headaches. The clinical utility of these agents is ever expanding, as they are gaining broader use in neuraxial analgesia, and new applications are continuously under investigation. The alpha2 agonists that are currently employed in anesthesia and pain management include clonidine, tizanidine, and dexmedetomidine. Moxonidine and radolmidine, which are not currently in clinical use in humans, may offer favorable side-effect profiles when compared with traditional alpha2 agonists, and may thereby allow for more widespread pain management applications.