Enhanced Recovery After Surgery (ERAS) protocols have been implemented in many institutions to attenuate the stress of surgery and facilitate early recovery. Careful selection of multimodal analgesic medication plays an essential role in achieving the goals of ERAS protocols. Clonidine and dexmedetomidine are α2-adrenergic receptor (α2-AR) agonists that can greatly enhance various ERAS components owing to their unique pharmacologic properties: antinociception, anxiolysis, anti-inflammation, and renal protection. The α2-AR agonists exert supraspinal and spinal antinociceptive effects by potentiating descending pain modulatory pathways and inhibiting peripheral C fibers. These antinociceptive effects of α2-AR agonists are independent of opioid receptors and result in analgesic synergy with opioid agonists. Several meta-analyses and systematic reviews have reported that α2-AR agonists decrease opioid consumption and side effects in adult and pediatric surgical patients. Given the wide distribution of α2-ARs in the body, α2-AR agonists have been associated with a reduction in anxiety, perioperative stress, inflammation, postoperative nausea and vomiting, shivering, and cognitive dysfunction. This course describes the basic and applied pharmacology of the α2-AR agonists and provides emerging evidence to support their utility in acute pain management and ERAS protocols. Perioperative administration of α2-AR agonists can enhance pain management, decrease adverse effects, and promote surgical recovery.