There is a critical mismatch between available organs for transplant and acutely or critically ill patients with end-stage organ disease. Patients who may benefit from organ transplantation far outnumber available organs. The causes for this imbalance are multiple. One cause is family refusal to donate. A second cause is nonrecognition or delay in determination of brain death. A third cause is donor loss due to profound cardiopulmonary and metabolic instability consequent to brain-stem herniation and brain death. Family refusal may be addressed by education, public awareness, as well as close attention to social, cultural and ethical issues, and optimal communication with donor families. Brain death may be consequent to traumatic brain injury, ischemic versus hemorrhagic stroke, as well as massive cerebral anoxia/ischemic following cardiac arrest. Nonrecognition or delay in brain death determination may be addressed by clinician education and frequent clinical assessment to detect early stages of brain-stem herniation refractory to aggressive measures for control of intracranial pressure. Donor loss due to profound cardiopulmonary and metabolic instability may be addressed by aggressive, mechanism-based treatment for clinical instability based on affected body system, as well as measures to support metabolic activity at the cellular and tissue level in the brain-dead organ donor. This article explores cerebral physiology related to impending brain death and catastrophic intracranial pressure elevations. In addition, physiologic consequences of brain death are correlated with affected body systems and mechanism-based therapies to support organ function pending transplantation. Ethical/legal issues are explored as related to patient autonomy and optimal family outcomes. Effective family communication, astute clinical assessment, and optimal clinical management of the organ donor are illustrated using a case study approach, highlighting the role of the advanced practice nurse in donor management.