The elucidation of the mechanisms by which gene expression is regulated has become a major focus of current biological interest. The mode of action of steroid hormones as gene regulatory molecules consequently has received great attention. Steroid hormones exert their effects in various target tissues through intracellular receptor proteins, which belong to a superfamily of transcription factors that regulate homeostasis, reproduction, development and differentiation. This superfamily includes receptors for steroids, thyroid hormones, vitamin A, and D derived hormones, and certain fatty acids, as well as transcription factors for which no ligand has been identified (the so called “orphan receptors”). All family members are intracellular transcription factors, and the true receptors mediate the biological effects of their respective hormones, primarily at the level of gene regulation, by binding to specific DNA sequences known as hormone response element (HRE) and by protein:protein interaction with other transcription factors. Each receptor protein is organized into several major functional domains. The major domains are those important for transactivation, site-specific DNA binding and ligand binding. The DNA binding domain (DBD), which is the most conserved region among this entire superfamily, is responsible for receptors’ ability to discriminate between their specific response element and other DNA sequences. The ligand domain (LBD) is responsible for discriminating between various ligands and is also the site for interation with certain other proteins. Transactivation domains may be found in the N-terminal region and/or within the LBD, depending on the particular receptor. The structure of some domains of a few of this receptor family have been solved. The three dimensional structure of the DBDs of the glucocorticoid, estrogen and retinoid X receptor, and of the LBD of the thyroid receptor with thyroid hormone bound, the retinoic acid receptor-g with all -trans retinoic acid bound, as well as the unliganded retinoid X and estrogen receptor have been solved. The secondary structure of the tau1 transcription activation region in the N-terminal domain of the glucocorticoid receptor has also been demonstrated. No complete structure or the structure of any two domains together is yet available for proteins of this family. We are interested in structure-function aspects of multiple domains of the human glucocorticoid receptor. Many structure-function aspects of these receptor proteins remain to be elucidated, such as the orientation of various domain in full length receptors, how they interact with respective HREs and other transcription factors, the role of heat shock proteins, structural changes during deactivation/activation process, and many more. Answers to these questions should be provided by three dimensional structures of these proteins, and this may eventually help in the better management of the therapeutic measures involving steroids and other hormones.