TBG, TTR, and albumin are quantitatively the most important thyroid hormone binding proteins in humans. Only a minute fraction of T3 and T4 circulates unbound, but it is this free hormone that is metabolically active at the tissue level, and, therefore, responsible for thyroid status. Inherited or acquired variations in the concentration or affinity of these proteins may produce substantial changes in serum total thyroid hormone levels but do not affect serum free thyroid hormone concentrations and, therefore, do not influence actual thyroid status. Thus, thyroid hormone-binding protein abnormalities must be suspected when abnormally elevated or diminished total thyroid hormone concentrations are encountered in clinically euthyroid subjects. This is crucial to avoid erroneous and potentially detrimental treatments for hyperthyroidism or hypothyroidism.