The description of two novel human defects in the last ten years has uncovered new aspects of thyroid hormone physiology with regard to cell-membrane transport and intracellular metabolism. Mutations in the X-linked monocarboxylate transporter 8 (MCT8) gene result in an invalidating neurodevelopmental phenotype in males and pathognomonic thyroid functions tests with high T₃, low rT_3, low or low normal T₄, and normal or slightly high TSH. Recessive mutations in the selenocysteine insertion sequence binding protein 2 (SBP2) gene present a variable clinical phenotype depending on the severity of the defect and its consequences on the selenoprotein hierarchy. Most characteristic is the thyroid phenotype of low serum T₃, high T₄, high rT₃, and slightly elevated TSH levels. Herein we review all known cases of MCT8 and SBP2 deficiency and describe each disease in terms of the clinical, biochemical, genetic, and therapeutic aspects.