The gene encoding pro-opiomelanocortin (POMC) presents unique regulatory features. In particular, glucocorticoids inhibit transcription of the POMC gene in the anterior pituitary, but not in the intermediate pituitary. In order to study the mechanism leading to transcriptional inhibition of POMC by glucocorticoid and the interaction of the glucocorticoid receptor complex with specific DNA sequences along the POMC gene, we have cloned the rat POMC gene and determined its structure. The gene is composed of three exons and appears to be present at a single copy per haploid genome. Besides the usual regulatory signals like 'TATA' and 'CCAAT' boxes, the upstream region contains sequences homologous to known enhancer sequences and to the glucocorticoid receptor binding site observed in glucocorticoid-responsive genes.