When brain injury is refractory to aggressive management and is considered nonsurvivable, with loss of consciousness and brain stem reflexes, a brain death protocol may be initiated to determine death according to neurological criteria. Clinical evaluation typically entails 2 consecutive formal neurological examinations to document total loss of consciousness and absence of brain stem reflexes and then apnea testing to evaluate carbon dioxide unresponsiveness within the brain stem. Confounding factors such as use of therapeutic hypothermia, high-dose metabolic suppression, and movements associated with complex spinal reflexes, fasciculations, or cardiogenic ventilator autotriggering may delay initiation or completion of brain death protocols. Neurodiagnostic studies such as 4-vessel cerebral angiography can rapidly document absence of blood flow to the brain and decrease intervals between onset of terminal brain stem herniation and formal declaration of death by neurological criteria. Intracranial pathophysiology leading to brain death must be considered along with clinical assessment, patterns of vital signs, and relevant diagnostic studies.