Nuclear receptor coregulators are proteins that modulate the transcriptional activity of steroid receptors, and may explain cell specific effects of glucocorticoid receptor action. Based on the uneven distribution of a number of coregulators in corticotropin-releasing hormone (CRH) expressing cells in the hypothalamus of the rat brain, we tested the hypothesis that these proteins are involved as mediators in the glucocorticoid induced repression of the CRH promoter. Therefore, we have assessed the role of the steroid receptor coactivator 1a (SRC1a), SRC-1e, and corepressors N-CoR and SMRT on both induction and repression of CRH in the AtT-20 cell-line, a model system for CRH repression by glucocorticoids. We show that the concentration of glucocorticoid receptor and the type of ligand, i.e. corticosterone or dexamethasone, determines the repression. Furthermore, overexpression of SRC1a, but not SRC1e, increased both efficacy and potency of the glucocorticoid receptor mediated repression of the forskolin-induced CRH promoter. Unexpectedly, co-transfection of the corepressors N-CoR and SMRT did not affect the corticosterone-dependent repression, but resulted in a marked decrease of the forskolin stimulation of the CRH gene. Altogether, our data demonstrate that 1) the concentration of the receptor, 2) the type of ligand and 3) the coregulator recruited, all determine the expression and the repression of the CRH gene. We conclude that modulation of coregulator activity may play a role in the control of the hypothalamus-pituitary-adrenal axis.