Abnormalities of thyroid hormone concentrations are seen commonly in a wide variety of nonthyroidal illnesses, resulting in low triiodothyronine, total thyroxine, and thyroid stimulating hormone concentrations. These thyroid hormone changes may be mediated in part by cytokines or other inflammatory mediators, acting at the level of the hypothalamus and pituitary, the thyroid gland, and the hepatic deiodinase system, as well as on binding of thyroxine to thyroid binding globulin. The degree of thyroid function disturbance correlates with disease severity and low levels of thyroid hormones predict a poor prognosis in several illnesses. It remains unresolved whether the hormone responses in the euthyroid sick syndrome represent part of an adaptive response, which lowers tissue energy requirements in the face of systemic illness, or a maladaptive response, which induces damaging tissue hypothyroidism. Consequently, the use of thyroid hormone therapy in the euthyroid sick syndrome is controversial. The small number of controlled trials performed to date have shown conflicting results on the cardiovascular effects of triiodothyronine, and none has had the statistical power to address the question of altered mortality. Future trials of therapy should concentrate on patients with severe nonthyroidal illness and a high mortality rate. Meanwhile, better understanding is needed of the impact of the altered thyroid hormone status on tissue function.