The undertreatment of acute pain associated with musculoskeletal conditions and surgical procedures is a focus of growing concern to orthopaedic surgeons. Fortunately, the armamentarium now includes recent advances in the understanding of how undertreated acute pain can lead to chronic pain, the development of new therapeutic agents, and new approaches to pain management. The concept of neuronal plasticity (the ability of neurons to profoundly alter their structure, function, or biochemical profile in response to repeated afferent sensory input) is now central to the understanding of the development of chronic pain from acute pain. Local inflammation in injured tissue increases the sensitization of specialized peripheral sensory neurons (nociceptors), leading to repeated afferent input into the central nervous system. Resolving inflammation before these events occur may prevent modifications in the central nervous system that lead to chronic pain. Therefore, it is important to reduce pain and inflammation at both the central and peripheral level. In addition to traditional agents (aspirin, nonspecific nonsteroidal anti-inflammatory drugs, opioids, local anesthetics, and regional blocks), more recently developed agents, such as cyclooxygenase-2 specific inhibitors, are now available. Combinations of these agents, as well as combinations of pharmacologic and nonpharmacologic approaches, are being used as multimodal therapy to treat the multiple sources of acute pain. Clinical practice guidelines for the management of acute pain now emphasize the incorporation of new knowledge into solid, evidence-based practice. This knowledge, combined with further understanding of the anatomic, physiologic, cellular, and molecular basis of pain, will provide the basis forfuture approaches to the management of acute pain in orthopaedic practice.