Adrenal glucocorticoid hormones, released in response to stress activation of the hypothalamic-pituitary-adrenal axis (HPA), are powerful regulators of cellular function. Analysis of early (10 min to <3 h) glucocorticoid inhibition of ACTH secretion from anterior pituitary corticotropes is providing insight into potentially generic genomic mechanisms by which glucocorticoids regulate cellular excitability. Early glucocorticoid inhibition is dependent upon activation of intracellular type II glucocorticoid receptors and induction of new proteins, including the calcium-binding protein calmodulin. Glucocorticoids inhibit ACTH secretion stimulated by neuropeptide activation of the cAMP/protein kinase A (PKA) or protein kinase C (PKC) signaling pathways through mechanisms acting at, or beyond, the level of intracellular free calcium mobilization. Increasing evidence also suggests that the efficacy of early glucocorticoid inhibition is selectively modulated by the PKA pathways. The integration of molecular, electrophysiological, imaging and classic neuroendocrine techniques will further expose the molecular basis of early glucocorticoid inhibition.