The nonthyroidal illness syndrome (NTIS) is a clinical condition of abnormal thyroid function tests observed in patients with acute or chronic systemic illnesses. The laboratory parameters of NTIS usually include low serum levels of triiodothyronine, with normal or low levels of thyroxine and normal or low levels of thyroid-stimulating hormone. It is still a matter of controversy whether the NTIS represents a protective adaptation of the organism to a stressful event or a maladaptive response to illness that needs correction. Multiple studies have investigated the effect of thyroid hormone replacement therapy in certain clinical situations, such as caloric restriction, cardiac disease, acute renal failure, braindead potential donors, and burn patients. Treating patients with NTIS seems not to be harmful, but there is no persuasive evidence that it is beneficial. The administration of hypothalamic releasing factors in patients with NTIS appears to be safe and effective in improving metabolism and restoring the anterior pituitary pulsatile secretion in the chronic phase of critical illness. However, also this promising strategy needs to be explored further. Anyhow, an extremely prudent approach is needed if treatment is given. Much of the data appearing in the literature on the treatment of NTIS encourage further randomized controlled trials on large number of patients. At present, however, we believe that there is no indication for treating thyroid hormone abnormalities in critically ill patients until convincing proof of efficacy and safety is provided.