In conditions of acute illness, patients present with reduced plasma T3 concentrations without a concomitant rise in TSH. In contrast, plasma concentrations of the inactive hormone rT3 increase, whereas plasma concentrations of T4 remain low-normal. This constellation of changes, referred to as nonthyroidal illness syndrome (NTIS), is present across all ages, from preterm neonates and over-term critically ill infants and children to critically ill adults. Although the severity of illness strongly correlates with the severity of the NTIS phenotype, the causality of this association remains debated, and pathophysiological mechanisms remain incompletely understood. In the acute phase of illness, NTIS appears to be caused predominantly by an increased peripheral inactivation of thyroid hormones, in which reduced nutritional intake plays a role. Current evidence suggests that these acute peripheral changes are part of a beneficial adaptation of the body to reduce expenditure of energy and to activate the innate immune response, which is important for survival. In contrast, in more severely ill and prolonged critically ill patients, an additional central suppression of the thyroid hormone axis alters and further aggravates the NTIS phenotype. Recent studies suggest that this central suppression may not be adaptive. Whether treatment of this central component of NTIS in prolonged critically ill patients, with the use of hypothalamic releasing factors, improves outcome remains to be investigated in large randomized control trials.