Both necrotizing enterocolitis (NEC) and congenital heart disease (CHD) are causes of significant morbidity and mortality in the neonatal population. While two distinct disease processes, NEC and CHD are inter-related as the incidence of NEC is greater in neonates with CHD than the normal newborn population. It is likely that circulatory perturbations, especially those seen in infants with left ventricular outflow tract lesions and single ventricle physiology, the stress of cardiac surgery and cardiopulmonary bypass, and the underlying baseline elevation of circulating endotoxin and proinflammatory cytokines all play a role in the pathogenesis of NEC in this uniquely susceptible population. The neurodevelopmental impairment in infants requiring surgery for NEC and in infants with complex congenital heart disease is alarming and requires further investigation. As medical and surgical advances allow for the palliation and correction of complex lesions at an earlier gestational age and lower birth weight, the already high risk of NEC in this population is likely to increase. This will require more aggressive study of the etiology of NEC in patients with CHD and the development of preventative therapies in order to decrease the impressive morbidity and mortality associated with the combination of these disease processes. In this article, we review the pathogenesis of NEC and CHD including associated mortality and morbidities and discuss possible mechanisms linking these two disease states.