Although rare, thyroid hormone resistance syndrome should be suspected on a biological profile combining high thyroid hormone and non-suppressed TSH plasma levels. Resistance to thyroid hormone can be classified into 3 forms: generalized, pituitary and peripheral, all three showing tissue resistance heterogeneity from one person to another, and from one tissue to another in the same subject. In the generalized and pituitary forms, thyroid hormone levels are high with paradoxically normal or increased TSH levels. The TRH test still stimulates TSH secretion, and only the highest doses of T3 successfully suppress TSH secretion. In the generalized form, euthyroidism is usual, whereas in the pituitary form hyperthyroidism requires treatment in order to lower TSH secretion. In the peripheral form, various symptoms of thyroid hormone deficiency may be observed, contrasting with normal T3, T4 and TSH serum levels, and requiring supraphysiological doses of T3 for correction. In most cases, familial occurrence can be evidenced, with an autosomal dominant or sometimes recessive mode of inheritance. Genetic analysis has identified, in the generalized form, more than 10 mutations of the thyroid hormone receptor beta gene, all resulting in an alteration in the T3 binding domain of the receptor. In the autosomal dominant form, tissue resistance may result from a "dominant inhibitory effect" of the normal receptor function by the mutant receptor. All these thyroid hormone resistance syndromes constitute exceptional models for studying the mechanisms of action of thyroid hormones. Simultaneous observations of the mutated receptors with various clinical and biological phenotypes should further our understanding of thyroid hormone receptor function.