Steroids and thyroid hormones, as well as vitamin D, retinoids and some nutrient metabolites (fatty acids, prostaglandins, farnesol metabolites) act by binding to members of the zinc-finger containing superfamily of nuclear hormone receptors. These receptor proteins bind directly to specific DNA recognition sequences (hormone response elements) in the promoter region of target genes, resulting in the alteration of the transcription initiation rate. While the principle of action of these receptors appears to be quite simple, the promiscuous behavior of some members of this family as well as cross-talk with other signaling systems result in an intricate regulatory network with distinct particularities for each receptor type. Specific areas of current interest in nuclear receptor research are: (i) the mechanisms for target gene specificity, which occur at the level of receptor expression, ligand metabolism and/or DNA sequence; (ii) cross-talk with other signaling systems resulting in the modulation of the transcriptional activity of the ligand-activated receptor through phosphorylation and/or heterodimerization with shared nuclear factors; and (iii) the discovery of novel agonistic and antagonistic ligands for established and orphan nuclear receptors. Recent insights through screening strategies for putative ligands, the cloning of co-activator proteins, as well as the characterization of human and animal models with germline and somatic mutations in nuclear receptors have resulted in important insights into some of the above questions, which are fundamental for a better understanding of the role of these hormone-activated transcription factors during development and cell differentiation.