Thyroid hormone (TH) transporters facilitate the cellular transmembrane passage of TH and are, consequently, required for proper TH signaling and metabolism in all target cells. Their pathophysiological significance is best illustrated in patients with inactivating mutations in the highly specific TH transporter MCT8 since affected patients display a severe form of psychomotor retardation (so called Allen-Herndon-Dudley syndrome) due to tissue- specific changes in TH homeostasis. MCT8 deficient patients as well as Mct8 mouse mutants exhibit abnormal serum TH profile in combination with an altered activity of the hypothalamic-pituitary- thyroid (HPT) axis indicating that TH transporter deficiency compromises the HPT axis on all levels. Here, I will briefly summarize recent studies of mice lacking Mct8 alone or in combination with other well-established TH transporters (Mct10 and Oatp1c1) as these studies shed light on many aspects and pathogenic events underlying global MCT8 deficiency. Moreover, development of conditional knock-out mice that allow a cell-specific inactivation of TH transporters in distinct cell types disclosed distinct cell-specific changes in TH signaling and sensing within the HPT axis. Altogether, our findings underscore the gate-keeper funtion of TH transporters as critical components in regulating local TH action.