Thyroid hormones are essential for normal mammalian development and for normal metabolism. Thyroxine (T4) is the principal product synthesized by the thyroid follicles, and triiodothyronine (T3), the biologically active hormone, derives mainly from tissue T4 deiodination. More than 99% of the circulating hormone is bound to plasma proteins, mainly to thyroxine-binding globulin, transthyretin and albumin in man, and to transthyretin and albumin in rodents. The role of plasma proteins in the transport of hormones to target tissues has, for a long time, been controversial. The liver and the choroid plexus are the major sites of transthyretin synthesis, tissues from which transthyretin is secreted into the blood and the cerebrospinal fluid, respectively. Transthyretin has been proposed to mediate thyroid hormone transfer into the tissues, particularly into the brain across the choroid-plexus-cerebrospinal fluid barrier. Studies in a transthyretin-null mice strain have shown conclusively that transthyretin is not indespensable for thyroid hormones' entry into the brain and other tissues, nor for the maintenance of an euthyroid status. An euthyroid status is also observed in man totally deprived of thyroxine-binding globulin and in rats without albumin. Taken together, these results exclude dependence of thyroid hormone homeostasis on any major plasma carrier per se. This evidence agrees with the free hormone hypothesis which states that the biologically significant fraction, that is taken up by the tissues, is the free circulating hormone.