Necrotizing enterocolitis (NEC) remains a leading cause of preterm infant mortality. NEC is multifactorial and thought to be a consequence of intestinal immaturity, microbial dysbiosis and an exuberant inflammatory response. Over the last decade, exaggerated TLR4 activity in the immature intestine of preterm neonates emerged as an inciting event preceding NEC. High TLR4 activity in epithelial cells results in the initiation of an uncontrolled immune response and destruction of the mucosal barrier. We will discuss the state of the science of the molecular mechanisms involved in TLR4-mediated inflammation during NEC and the development of new therapeutic strategies to prevent NEC.