Preterm infants, age-corrected for prematurity, score on average, 10 points lower on IQ tests than full-term infants tested at comparable ages. This review focuses on the potential contribution of the hypothalamus to cognitive neuro-regulatory development in preterm infants through its bidirectional neural connections with the prefrontal cortex and its neuroendocrine activity. It aims to clarify the central role of the hypothalamus in preterm high stress situations and in influencing cognitive development via its connectivity to the cerebral cortex. The review further evaluates epigenomic sensitivity to environmental inputs. Recent results suggest that an optimal range of DNA methylations (via a continuous process of decreasing levels of receptor methylations that are too high, and increasing levels that are too low) appears necessary in order to reach an adaptive level of receptor availability. Several studies have demonstrated amelioration of preterm infants' stress while in the Newborn Intensive Care Unit (NICUs) and following discharge. The authors postulate that feedback mechanisms and correction signals are the basis for a hypothalamic homeostatic modulating function, a "hypothalamic resistance response", which may account for the stress reduction brought about by in- and post-NICU early interventions and their results of promoting self-regulation and cognition.