IN 1927, UHLENHUTH (1) demonstrated that the anterior lobe of the pituitary gland of salamanders produces a factor capable of controlling the function of the thyroid. This factor was subsequently called TSH. Forty years later, Pastan and co-workers (2) demonstrated that TSH exerts its effects through a protease-sensitive structure on the thyroid cell plasma membrane, thus postulating the existence of a specific receptor (TSH-R; the current official name is Tshr for mouse genetic locus and TSHR for the human locus). The relevance of the interaction between TSH and its receptor in the physiology and pathology of the thyroid became immediately clear, and indeed in 1968 Stanbury (3) suggested that congenital hypothyroidism in the absence of goiter could be due to an impaired response to TSH. The mechanisms triggered by Tshr upon interaction with the ligand, which regulate both proliferation and function of thyroid cells, have been exhaustively studied mainly in cell culture models. Several comprehensive reviews summarize these aspects of TSH signaling (4–8). This review will focus on a different aspect of TSH signaling, its role in the development and differentiation of the thyroid, as determined by the study of alterations in this pathway in both mice and humans. Indeed, these studies have provided important insights about the physiological roles of TSH/Tshr signaling, in some cases underscoring the pivotal role that this system plays in regulating the size and function of the thyroid gland; in others demoting it to, at best, a marginal modulator. Furthermore, the animal models have been useful in discovering new important functions of such signaling systems in extrathyroidal tissues (9), which are beyond the scope of this review.