The chronicity of pain is the feature of pain that is least understood and most directly linked with our inability to effectively manage pain. Acute pain is relatively responsive to our current pharmacologic and interventional armamentarium. However, as pain persists, our ability to treat effectively diminishes and the patient's frustration and resource utilization increases. This article explores our current understanding of the factors linked to pain duration and the transition from acute to chronic pain in both human and animal models, and across a spectrum of human chronic pain conditions.