An intense systemic inflammatory response to illness or injury is a key mediator of organ dysfunction during critical illness. Several conditions that often lead to an ICU admission are examples of the deleterious effects of systemic inflammation (eg, severe sepsis, trauma, acute respiratory distress syndrome). Proinflammatory cytokines (eg, tumor necrosis factor [TNF]-α and IL-1β) and chemokines (eg, monocytic chemoattractant protein [MCP]-1) activate leukocytes and endothelial cells (which express leukocyte adhesion molecules), resulting in endothelial damage and tissue factor expression that initiate a procoagulant cascade, ultimately leading to microvascular thrombosis, impaired blood flow, and end-organ damage (Fig 1). In addition, cytokines trigger production of inducible nitric oxide synthase (iNOS), which causes nitric oxide-mediated hypotension, further inflammation, and apoptosis. Ultimately, the characteristic inflammatory state of critical illness causes multiple mechanisms of injury in the brain, including vascular damage, ischemia, breakdown of the blood-brain barrier (BBB), local neuroinflammation, and apoptosis, all of which are observed, for example, in animal models of sepsis and in humans with sepsis-associated delirium.9,10 In addition to directly injuring neurons, this neuroinflammation activates quiescent microglia, the resident macrophages in the brain (Fig 1),10‐12 a process that van Gool and colleagues13 proposed as pivotal to CNS damage from systemic inflammation. Microglia are usually activated to clear apoptotic cells resulting from an injury.14 Their overactivation, however, can be responsible for an exaggerated inflammatory response.14 Van Gool and colleagues,13 in fact, postulated that impaired cholinergic inhibition of microglia is responsible for overactivation of microglia that can persist for months following critical illness, contributing to ongoing neuroinflammation, with resultant neurodegeneration manifesting as severe prolonged delirium and LTCI.