Postoperative delirium (POD) is a neurobehavioral syndrome caused by dysfunction of neural activity mainly in elderly people. POD is not uncommon, but under-recognized, and often serious. Multifactorial causes including aging, acetylcholine deficiency, sleep deprivation and intraoperative hypoxia have been proposed attempting to explain the processes leading to the development of POD. To date, however, no specific pathophysiologic mechanism has been identified. Here, we summarize the five most prominent theories (neuronal aging, neuroinflammation, neurotransmitter imbalance, neuroendocrine activation, and network connectivity change) to explain the development of delirium. Understanding of the neuropathogenesis of delirium will help focus future research, and assist in developing prophylactic and treatment strategies.