During the past four decades major advances in the management of premature infants have led to progressive reduction in mortality. During this period mortality in very low birth weight infants (VLBW, <1500 grams and <30 weeks gestation age) has decreased, and more than 50% of infants less than 24 weeks gestation age now survive, increasing the population of VLBW infants in intensive care nursery environments. Thyroid function in these infants is characterized by decreased TSH and T4 responses to parturition, low serum total T4 and TSH levels and variable free T4 concentrations during the first 2-4 postnatal weeks of life. These features reflect a state of transient hypothalamic-pituitary or central hypothyroidism. There is a high prevalence of morbidity in these infants, as well, often associated with further reductions in serum total T4, T3, TBG and TSH concentrations and variable levels of free T4 and reverse T3, resembling the non-thyroidal illness (NTI) syndrome in adults. The etiologic roles of thyroid system immaturity and NTI in the transient hypothyroxinemia of prematurity (THOP) and the impact of THOP on the subsequent neurological deficits in VLBW infants remains unclear. Several thyroxine supplementation trials have been conducted with inconclusive results. Further studies are planned or in progress.