Adverse experiences early in life have the potential to disrupt normal brain development and create stress response channels in preterm infants that are different from those observed in term infants. Animal models show that epigenetic modifications mediate the effects of maternal separation and environmental stress on susceptibility to disease and psychobehavioral problems later in life. Epigenetic research has the potential to lead to the identification of biological markers, gene expression profiles, and profile changes that occur overtime in response to early-life experiences. Combined with knowledge gained through the use of advanced technologies, epigenetic studies have the promise to refine our understanding about how the brain matures and functions from multiple perspectives including the effect of the environment on brain growth and maturation. Such an understanding will pave the way for care practices that will allow the premature brain to develop to its full capacity and will lead to the best possible outcomes. Neonatal epigenetic research is emerging and rapidly advancing. As scientists overcome biological, technical, and cost-related challenges, such research has a great potential in determining key environmental factors that affect the preterm genome, allowing for targeted interventions. The purpose of this article is to explore existing literature related to epigenetic mechanisms that potentially mediate the effects of the environment on preterm infant brain development.