Pentalogy of Cantrell is a syndrome consisting of (1) a midline, supraumbilical abdominal wall defect; (2) a congenital heart defect; (3) a lower sternal defect; (4) an anterior diaphragmatic defect; and (5) a diaphragmatic pericardial defect. Patients present a challenge to both the surgeon and anesthesiologist in the operating room due to the wide spectrum of anomalies with various complexities they bring. Planning dictates a multidisciplinary approach involving neonatology, cardiology, cardiac surgery, general surgery, anesthesiology, and pertinent subspecialties to determine the best course of action. Generally, corrective strategies include separation of the peritoneal and pericardial cavities with coverage of midline defects, omphalocele correction, repair of intracardiac lesions, and restoration of the heart into the thoracic cavity, all while preserving/establishing musculoskeletal structural integrity and hemodynamic stability. The potential for significant cardiopulmonary compromise is high and must be understood and anticipated when caring for these patients.