The syndromes of resistance to thyroid hormone (RTH) are rare disorders characterized by elevated levels of circulating free thyroid hormones, inappropriate TSH secretion and variably reduced peripheral tissue responses to iodothyronine action. On the basis of clinical features, two major forms of RTH are recognized: generalized resistance (GRTH) in which patients are asymptomatic with few clinical signs, and pituitary resistance (PRTH) where patients present with features associated with thyrotoxicosis. However, a review of the literature and our own experience indicates that there is a wide overlap of clinical and biochemical features between individuals with GRTH or PRTH. Genetic analysis shows that both disorders are associated with a number of different mutations in the thyroid hormone receptor beta (TR-beta) gene which localize to two regions in the hormone-binding domain. The mutant proteins are transcriptionally impaired but preserve the ability to bind DNA, dimerize and inhibit the function of their wild-type counterparts in a dominant negative manner. Dominant negative effects of mutant receptors within the pituitary-thyroid feedback axis generate abnormal thyroid function test results characteristic of RTH. The variable peripheral resistance may be related to differences in tissue distribution of TR-alpha versus TR-beta receptor isoforms, variable dominant negative effects of mutant receptors on different target genes or other factors not related to the receptor mutation. Although GRTH and PRTH represent the variable phenotypic spectrum of a single genetic entity, this clinical distinction will remain useful as a guide to appropriate treatment.