Investigating an unexpected death during hospitalization poses a unique set of challenges to the pathologist. Complex medical history and hospital course are the norm rather than the exception. The autopsy examination must distinguish between expected changes arising from disease and therapy and unexpected findings that suggest a cause of death. Reviewing the medical record, including surgical, radiologic, and laboratory findings, is crucial in guiding the autopsy and the interpretation of autopsy findings. Many causes of unexpected death in the hospital may be difficult to detect at autopsy in the absence of a clinical suspicion. Some situations may require collection and/or preservation of pre- or postmortem fluids or tissues, such as serum or liver to detect drug levels, or vitreous humor or urine to determine electrolyte, glucose, and ketone levels. In some cases, special dissection techniques may be required. Common causes of unexpected death and injury in the hospital include medication errors and adverse reactions, surgical and anesthesia complications, nosocomial infections, and transfusion reactions. Clinical suspicion is important in guiding autopsy technique, ancillary testing, and interpretation of findings. The autopsy also plays a unique role in hospital quality control and in detecting complications arising from new therapies and techniques.