Thyroid hormones orchestrate developmental processes and are among the most important regulators of energy metabolism. Thyroid hormone actions are mostly, but not exclusively, mediated by nuclear hormone receptors. As amino acid derivatives, thyroid hormones need plasma membrane transporters in order to reach their nuclear receptors. Several transporters from different gene families mediate thyroid hormone uptake into cells. Monocarboxylate transporter 8 is a specific thyroid hormone transporter found mutated in patients with severe psychomotor retardation and strangely abnormal thyroid hormone constellations. These patients display a syndrome in which some organs are exposed to increased thyroid hormone signaling, while other organs are lacking thyroid hormone signaling due to complete lack of thyroid hormone uptake. Investigations in many organ systems using mouse models of thyroid hormone transmembrane transporter deficiency have helped complete our picture of thyroid hormone metabolism and action in the body during development and under different physiological conditions. Incorporating the concept of thyroid hormone transmembrane transport has helped understand previously enigmatic drug interactions and may explain how the hormonal set points in the hypothalamus-pituitary-thyroid axis are established.