Necrotizing enterocolitis (NEC) is a devastating and common disease of very low birth weight (VLBW) infants with a mortality rate of 10% to 50% and a significant cause of morbidity in survivors. The incidence of NEC has increased from 5% to 7% in the last decades and this rate is likely to rise because of the increased survival of infants born at 24 weeks gestation, which are at high risk of developing NEC. NEC etiology is multifactorial: ischemia, infections, cytokines, enteral feeding and reactive oxygen species or free radicals (FRs) may contribute to the disruption of the immature gut barrier. In particular, ischemia, hypoxia-reperfusion, infection and inflammation are mechanisms capable of producing high levels of FRs, perturbing the normal redox balance and shifting cells to a state of oxidative stress (OS). Despite advances in neonatal medicine, the early diagnosis of NEC remains a major challenge. Early clinical signs are non specific and the laboratory findings are not fully reliable. Therefore, its delayed occurrence after birth, its rapid onset, the highly fulminant nature, and its severe morbidity, as well as the possibility of progression to death, strongly require the identification of new prospective biomarkers specific for high NEC risk. There is evidences that OS biomarkers in cord blood allow the early identification of infants at risk for NEC and thereby can be used to develop novel therapies for this devastating disease which predominantly occurs in premature infants.