In preterm infants, necrotizing enterocolitis (NEC) is one of the most devastating complications seen in the neonatal intensive care unit (NICU), with both short- and long-term sequelae. Outcomes reported for mono- (versus di-) chorionic twins suggest an increased incidence in the monochorionic twins, usually attributed to abnormal placental vascular connections. Same sex concordance and zygosity data suggest shared genetic and environmental factors as important contributing factors to the pathogenesis of NEC. This concept is further supported by fecal microbiome data from preterm twins. However, there is also some uncertainty in these observations because studies that controlled for gestational age did not show significant differences between singletons and twins in the occurrence of NEC. This mini-review was undertaken as a critical appraisal of the published literature in terms of twin studies to establish the genetic relevance vis-àvis NEC. There is a need for further evaluation of genetic and confounding factors arising from the environment and the gut microbiome in these infants using cohorts with larger sample sizes.