The pain that accompanies surgical procedures remains prevalent and is an aspect of the perioperative experience that generates the greatest concern for patients about to undergo surgery. There is also a growing recognition of the extent that acute painful experiences can lead to longer-term painful consequences, even when tissue healing appears to be complete. The neurobiologic basis of this has been partially elucidated. The key observations are that multiple sites and multiple receptors collectively contribute, and that noxious stimuli initiate a cascade of events that sensitise the nervous system so that subsequent noxious stimuli are perceived with greater intensity and even previously non-painful stimuli can be painful. Incorporating these observations into effective perioperative regimens designed to limit acute pain and its consequences leads to a multimodal pre-emptive approach to acute pain management. Acute perioperative pain is an ideal setting for the use of pre-emptive analgesic techniques because the timing of noxious stimuli is known in advance and surgical sensitisation of the nervous system is ongoing despite adequate levels of general anaesthesia with volatile anaesthetics. The relevant neurobiology of pain, reviewed in this article, is the basis for advocating an aggressive, multimodal, pre-emptive approach to acute pain therapy throughout the entire perioperative period. A growing body of outcome studies demonstrates the long-term efficacy of this approach.