Pediatricians, neonatologists and pediatric endocrinologists are often challenged with determining the significance of atypical thyroid and adrenocortical function studies in preterm, low birth-weight (gestational age <37 weeks; birth-weight <2500 g), very low birth-weight (gestational age <30 weeks; birth-weight <1500 g) or extremely low birth-weight (gestational age <27 weeks; birth-weight <1000 g) neonates. The neonatal period is defined as the first 30 days after birth. Often, these neonates are critically ill and being treated with several medications that further confound their evaluation and therapeutic management. Physicians who care for these patients are regularly faced with the questions: What are normal values of thyroid hormones and cortisol in preterm neonates? What is the significance of hypothyroxinemia or hypocortisolemia in these subjects? When is hormone-replacement therapy warranted? In this review, the physiology of thyroid and adrenocortical hormone secretion in the fetus and neonate is discussed and reference data for serum concentrations of thyroid and adrenocortical hormones in preterm and full-term neonates is presented. The evaluation and hormonal management of neonates with hypothyroxinemia and hypocortisolemia are outlined and critically analyzed. © 2010 Future Medicine Ltd.