Delirium, or acute brain dysfunction, is a life-threatening global disturbance in cognitive functioning that frequently manifests in critically ill patients. This review examines the current status of knowledge regarding the pathophysiology of delirium in the ICU, in particular, evaluating the role of iatrogenic factors such as sedatives and analgesic administration in brain dysfunction. This hypothesis is considered along with several other plausible mechanisms of ICU delirium, including sepsis, postoperative cognitive dysfunction, and changes in biomarkers and neurotransmitters. The review concludes by highlighting potential future directions in molecular genetics for the elucidation of delirium and its long-term consequences.