Sonic hedgehog (Shh) is a signaling protein that binds to Patched and mediates its effects through Gli transcription factors. Shh is important in regulating survival and growth in both the embryo and the adult. It is known to be involved in pituitary development, but its role in the adult pituitary has not been investigated. Here, we show Shh and Gli1 immunoreactivity in adult human corticotroph cells. Administration of Shh (5 microg/ml) alone and in combination with corticotrophin-releasing hormone (CRH; 100 nM) in dispersed rat anterior pituitary and AtT-20 mouse corticotrophinoma cells increased corticotrophin (ACTH) secretion and pro-opiomelanocortin (POMC) promoter activity. Shh and CRH act additively in increasing CRH receptor 1 (CRH-R1). Unexpectedly, we found that CRH on its own increased Gli-dependent transcription, which in turn stimulated POMC transcription. Gli1 is necessary for CRH signaling, since knocking down Gli1 by RNA interference abolished the stimulatory effect of CRH on POMC. Taken together, our results demonstrate a new role for Shh and Gli1 in corticotroph function and provide a new link between Shh and CRH signaling pathways.