Pro-opiomelanocortin (POMC) is the pituitary precursor for adrenocorticotropin (ACTH), beta-endorphin, beta-lipotropin and the melanotropins. The level of ACTH secretion from the anterior pituitary is largely determined by the competing action of the stimulatory hypothalamic hormone, corticoliberin (corticotropin-releasing hormone, CRH), and the inhibitory effect of glucocorticoids. We now demonstrate that these two hormones, glucocorticoids and CRH, also inhibit and stimulate, respectively, the transcription rate of the POMC gene as measured by nuclear run-on transcription assays. Indeed, we show both by in vivo treatment and with rat anterior pituitary cells in primary culture that glucocorticoids inhibit within 30 min transcription of the POMC gene. Similarly, we find that CRH stimulates POMC gene transcription within 15 min. CRH and glucocorticoids can compete with each other to set the rate of POMC transcription. Our results indicate that CRH and glucocorticoids regulate anterior pituitary POMC gene transcription in addition to their well-documented role in the control of POMC peptide release.