Most cellular actions of the steroid and thyroid hormones, vitamins A and D, and other small lipophilic molecules are mediated through binding to nuclear receptors, which act as ligand-inducible transcription factors by recruiting coactivators and corepressors. Steroid receptors bind as homodimers to hormone-response elements (HREs) in target genes, while non-steroid receptors generally bind DNA as heterodimers with the retinoid X receptor (RXR). Our understanding of nuclear receptor actions has been significantly improved by the existence of natural mutations that cause hormone resistance syndromes. Biochemically, patients with thyroid hormone, androgen or glucocorticoid resistance have unappropriately high levels of TSH, LH, or ACTH due to lack of feedback inhibition on the hypothalamus and pituitary gland, and to reduced sensitivity of other target tissues. Several hormone resistance syndromes are inherited in an autosomal dominant manner, because the mutant receptor inhibits transcription by the WT receptor, displaying dominant negative activity. These disorders can be due to point mutations in the receptor DNA -binding domain (DBD), preventing DNA binding. Other mutations are located in the ligand-binding domain (LBD) and can disrupt dimerization or ligand binding, resulting in impaired coactivators recruitment and reduced corepressor release. In a few cases, hormone binding and dimerization are normal, but mutations occur in the carboxi-terminal AF-2 domain responsible for association with coactivators. Interestingly, we have observed that in heterodimeric receptors such as TR or VDR the presence of the RXR ligand or the interaction with non-classical coactivators such as β-catenin can partially restore transcriptional activity of AF-2 mutants. A point TR AF-2 mutant also preserves the anti-transforming and anti-tumorigenic actions of the WT receptor. The combination of cell-based studies, animal models and investigations in affected humans hopefully will help us to understand the disorders due to defects in nuclear receptors and to improve their diagnosis and management.