THE INTRACELLULAR receptor proteins for steroid hormones are a group of transcriptional regulatory proteins with several common features, acting by direct interaction with DNA. The protein must first be activated by the binding of the appropriate class of steroid. The steroid hormone receptor proteins, in particular the glucocorticoid receptor, and their role in gene regulation represent the best characterized eukaryotic gene regulating systems today, with major recent advances in knowledge of structure and function of both the protein and DNA components involved. During the 20 yr of research in this field, there are several major landmarks that have contributed to our understanding of gene regulation by steroid hormones, particularly by glucocorticoids, namely: 1) the synthesis of tritium-labeled steroids with high specific activity (1); 2) the demonstration of a high affinity, low capacity binding species, the putative receptor protein, for glucocorticoids (for review, see Refs. 2–5); 3) the interaction of the receptor with the nucleus or DNA (2–5); 4) the demonstration that glucocorticoids can regulate specific genes, their messenger RNAs (mRNAs) and their transcription (2–5); 5) the purification of the glucocorticoid-receptor complex (GR) (6–8); 6) the demonstration of specific GRbinding sequences within the genome (9); 7) the demonstration by gene transfer of glucocorticoid-responsive sequences (10); 8) the cloning of complementary DNA (cDNA) for the glucocorticoid (11–13), estrogen receptor (ER) (14–16), and progesterone (17–19) receptors (PR).