Resistance to thyroid hormone (RTH), Refetoff's syndrome, is a syndrome of reduced responsiveness of target tissue to thyroid hormone (TH). Inheritance is usually autosomal dominant except in one family, being recessive. Since a point mutation was first discovered in the thyroid hormone receptor (TR) beta gene of a subject with RTH, approximately 93 unrelated families with RTH have been found to have mutations on TR beta gene. Clinically they presented either generalized (GRTH) or dominantly pituitary (PRTH) resistance to TH. In one family, affected consanguineous individuals lacked the entire protein coding region of both hTR beta alleles. In this family with recessively inherited RTH, the obligate heterozygous parents exhibited no clinical and laboratory abnormalities. Thus, manifestation of RTH in heterozygous individuals required the expression of a mutant receptor that interferes with the function of normal allele ("dominant negative effect"). The formation of mutant TR/TRAP (RXR etc.) heterodimer or mutant TR homodimer having the capability to bind the DNA for this dominant negative suppression of mutant TR beta, and the variation of TRE types, receptor isoforms and auxiliary proteins depending on the target tissue may play an important role in the manifestation of TH resistance. This may explain in part the intra- and inter-individual differences in organ resistance in patients with RTH. Studying the errors of nature would contribute to understand the molecular mechanism of TH action.