Necrotizing enterocolitis (NEC) presents as the most common gastrointestinal emergency during the neonatal period and results in ulceration and necrosis of the distal small intestine and proximal colon. The etiology of NEC remains unknown. Based on the complexity of gut development, multiple growth factors and cytokines may be needed to synergistically support the developing gut. Epidermal growth factor (EGF) has been shown to play an important role in intestinal cell restitution, proliferation, and maturation. EGF is found in abundant quantities in many fluids, including the gastrointestinal tract, amniotic fluid, breast milk, and saliva. Preliminary clinical trials using EGF in neonates diagnosed with NEC have been shown to promote repair of intestinal epithelium. Additionally, other growth factors are also emerging as potential treatment modalities, including erythropoietin, granulocyte colony stimulating factor, and heparin-binding EGF. The role of EGF and other growth factors in the pathogenesis and prevention of NEC will be reviewed.