Necrotizing enterocolitis is one of the most frequent and severe gastrointestinal diseases that affect preterm newborns in Neonatal Intensive Care Units. It was firstly described in 1960s, but this clinical entity was not widely recognized until the advent of modern neonatal intensive care. The disease is characterized by submucosal edema, infiltration of intestinal wall by immune cells, specifically neutrophils and, in severe forms, wall necrosis that leads to intestinal perforation. Its incidence is inversely associated to birth weight and gestational age. Necrotizing enterocolitis has been responsible for high rates of morbidity and mortality (15-30%), despite improvements made in neonatal care in the last decades. The challenge is to optimize strategies for early diagnosis, define the best medical and surgical treatments and standardize preventive measures. Several biomarkers have been proposed for the early prediction of necrotizing enterocolitis onset in preterm newborns and can be useful not only for diagnostic purposes but also for prediction of disease progression and severity. The purpose of this paper is to illustrate the most recent evidence regarding the diagnosis and prevention of necrotizing enterocolitis. This manuscript contributes to clinical decision-making in preterm neonates at high risk of developing necrotizing enterocolitis.