Thyroid gland function develops and matures during fetal life, with production of serum thyroxine (T4) concentrations beginning around 12 weeks gestation and increasing to term. Infants born prior to term have lower cord serum T4 concentrations that correlate with gestational age or birth weight. This is partially the result of lower thyroxine-binding globulin (TBG) concentrations. The cord serum free thyroxine (FT4) concentrations also correlate with gestational age, but they are not proportionately as low as the cord T4 concentration. Preterm infants have a postnatal thyrotropin (TSH) surge and rise in serum T4 and triiodothyronine (T3), which is qualitatively similar to, but quantitatively smaller than, term infants. In contrast to term infants, preterm infants often experience a fall in serum T4 and T3 in the first week of life to below birth levels. This drop appears to be the result of many factors, including nutritional problems and decreased hepatic TBG production, immaturity of hypothalamic-pituitary control of the thyroid gland, immaturity of the thyroid gland itself, and increased tissue utilization of T4. These changes are impacted by complications of prematurity, such as respiratory distress syndrome (RDS), which result in nonthyroidal illness-like changes. Again, serum FT4 seems less affected, and when measured by equilibrium dialysis may be in the normal range for age. Several studies have correlated different measures of morbidity and mortality in the preterm infant with lower serum T4 concentrations. However, as with adults, it may be that low serum T4 concentrations are a marker of the sickest preemies. Also, as with adults, this has led to speculation that T4 treatment might be beneficial in improving these complications of prematurity, in particular the neurological outcome. While some studies appear to show improvement in some facet of medical complications with T4 treatment, most show no effect. Regarding neurological outcome, the 2 best controlled trials do not show improvement in neuropsychiatric testing outcome assessed up to 2 years of age. One study, however, showed an IQ that was 18 points higher in the T4-treated subgroup less than 27 weeks gestational age. It may be that the most preterm infants, eg, those less than 27 weeks of age, are at a disadvantage compared with their intrauterine counterparts, in that they lack the maternal thyroid hormone contribution and are forced to adapt to extrauterine life before their hypothalamic-pituitary-thyroid axis is mature enough to deal with tissue thyroxine demands. Further controlled studies are needed to determine if this subgroup of infants indeed may benefit from transient thyroid hormone supplementation.