Pronounced alterations in plasma thyroid stimulating hormone and thyroid hormone levels occur during critical illness without any evidence for thyroid disease. Plasma T3 decreases and plasma rT3 increases within a few hours after the onset of disease, and the magnitude of these changes is related to the severity and the duration of the disease. This article reviews the mechanisms behind the observed changes, and focuses on the regulation of thyroid hormone deiodination and transport, as well as the potential positive or negative effects for both the acute and the chronic phase of critical illness.