G protein-coupled receptors (GPCRs) are involved in the pathophysiology of a wide range of diseases and constitute an attractive therapeutic target. In the thyroid gland, TSH receptor (TSHR), a member of the GPCR family, is a major regulator of thyroid differentiation and function. Alterations in TSHR activity are often involved in the development of pathologies such as thyroid cancer and thyroid enlargement (goiter). Here we show that DREAM (downstream regulatory element antagonist modulator) modulates TSHR activity through a direct protein-protein interaction that promotes coupling between the receptor and Gαs. In transgenic mice, DREAM overexpression provokes a marked enlargement of the thyroid gland. Increased levels of DREAM protein were observed in human multinodular goiters, suggesting a novel etiopathogenic mechanism in nodular development in humans. Taken together, these findings identify a mechanism for the control of TSHR activity and provide a new approach for the study and treatment of thyroid pathologies associated with impaired TSHR function.