Thyroid hormone (TH) is a critical regulator of human development, growth, metabolism and neurologic function. Additionally, TH controls its own synthesis by regulating TSH production from the pituitary. Indeed, the TSH assay is the most widely used biomarker to determine TH action in humans. Importantly the actions of TH are mediated genomically by its cognate nuclear receptors, the thyroid hormone receptor isoforms (TRs) which act in the presence or absence of TH to regulate gene expression by recruiting separate classes of co-regulatory proteins depending upon the presence of ligand. Surprisingly, despite the importance of TH-signaling, little is known about the role of TR and its co-regulators in mediating cell-specific effects of TH and in the mechanisms of positive and negative regulation by TH. Using a variety of mouse models, we demonstrate that TR co-regulators are important in determining cell sensitivity to TH as well as in determining the set point of TSH secretion. Furthermore, dysregulated co-regulator recruitment by mutant TRs mediates the syndrome of Resistance to Thyroid Hormone in vivo. These results demonstrate that TH action in target tissues can be independent of the circulating TSH level. Furthermore, this suggests that individual responses of tissues and body systems in humans to TH could vary independently of the TSH. Thus, it is likely that additional biomarkers will be necessary to interrogate TH action in patients to determine optimal therapy with either TH or its potential analogues under clinical development.