The pathogenesis of NEC is multifactorial and involves complex interactions between clinical risk factors, intestinal microbiota, and the immature intestinal immune system. A critical gap in our knowledge of the factors that determine interindividual variability in NEC susceptibility, combined with an absence of robust biomarkers, has limited early screening and prevention-based strategies to prevent NEC. Epidemiological data indicating differences in prevalence among different ethnicities, as well as data from twin studies, led to the recognition that genetic factors might modulate the susceptibility and severity of NEC. Several potential pathogenic variants for NEC in premature infants have been investigated, and with advances in genomic research, it is expected that more genetic variants and loci of interest will be uncovered. Most studies to date have not been validated by adequately powered replication cohorts or functional studies. Despite these limitations, genetic research in NEC provides new insights into the pathogenesis of disease and could potentially uncover new strategies for disease prevention and targeted therapy, leading to more individualized care. In this chapter we review the published literature with respect to genetic association studies in NEC and provide an overview of the challenges, opportunities, and approaches for future research in this rapidly evolving scientific field.