PURPOSE OF REVIEW: Persistent postoperative pain (PPP) is a significant source of morbidity in our population. An excellent opportunity to understand the transition from acute to chronic pain states. Understanding the mechanisms that drive this and modulators that influence this transition is essential to both prevent and manage this condition. RECENT FINDINGS: Although the exact mechanism for the development of PPP is still poorly understood, hypotheses abound. Basic science research with animal models implicates nociceptive and neuropathic pain signals leading to pain sensitization due to persistent noxious signaling. Effects on the inhibitory modulation of noxious signaling in medullary-spinal pathways and descending modulation have also been implicated. SUMMARY: Persistent maladaptive neuroplastic changes secondary to neurotrophic factors and interactions between neurons and microglia may well explain the phenomenon. This article reviews the current thought processes on mechanisms and modulators from a basic science and epidemiological perspective.