X-linked adrenal hypoplasia congenita (AHC) is an inherited disorder of the development of the adrenal cortex. The gene responsible for this genetic disorder has been identified using positional cloning methods and has been named DAX-1 based on its localization within the dosage-sensitive sex reversal (DSS) locus and the AHC locus on the X chromosome. The DAX-1 gene consists of two exons separated by a 3.4 kb intron. Analysis of DNA from patients with deletions in the AHC critical region in the X chromosome provided strong indication for the involvement of the DAX-1 gene in X-linked AHC. A number of intragenic mutations within the DAX-1 gene have also been identified in patients with isolated AHC. The DAX-1 gene product belongs to the nuclear hormone receptor superfamily based on the presence of an entire ligand binding domain present in the carboxy-terminal region of the receptor. However, DAX-1 has a domain structure which is very unusual with respect to other nuclear hormone receptor superfamily members. The amino-terminal portion of DAX-1 contains a novel domain consisting of 3.5 repeats of a 65-67 amino acid motif that contains two putative zinc finger structures in place of the more usual amino-terminal domain, DNA binding domain, and hinge region of the typical nuclear hormone receptors. It has been proposed that the amino-terminal portion of the DAX-1 protein is the DNA binding domain. The expression pattern of DAX-1 suggests that it may play a role in the regulation of steroidogenesis. Not only is DAX-1 expressed in the adrenal glands, but it is also expressed in the ovaries and testes. Most recently, we demonstrated that DAX-1 is also expressed in the hypothalamus and pituitary gland. The expression of DAX-1 in the neuroendocrine system suggests that interruption of the expression in these tissues may be the cause of the hypogonadotropic hypogonadism (HH) that is frequently associated with AHC. Interestingly, hybridization of a human DAX-1 cDNA probe with genomic DNA from various species indicated that a DAX-1 homologue may exist in yeast. Thus, DAX-1 or a DAX-1-like transcription factor may be the most primitive member of the nuclear hormone receptor superfamily. Although the molecular mechanism of action of DAX-1 is not yet characterized, its importance for the development and physiology of the adrenal gland and gonads is indicated by its involvement in AHC and HH. Analysis of the functions of DAX-1 along with its regulation of expression will not only provide information concerning the actions of this new member of the nuclear hormone receptor superfamily, but will also yield insight into the pathogenesis of AHC and HH and may allow for the development of gene therapy protocols for the treatment of these diseases.