The activity of the hypothalamicpituitaryadrenal (HPA) axis is characterized by an ultradian (pulsatile) pattern of glucocorticoid secretion that is critical for optimal transcriptional, neuroendocrine and behavioural responses to glucocorticoids. We have investigated the molecular mechanisms underlying the origin of glucocorticoid ultradian rhythm within the rat adrenal gland. We show that this rhythm of glucocorticoids depends on highly dynamic processes within adrenocortical steroidogenic cells, that includes rapid phosphorylation of proteins involved in the acute corticosterone response to a pulse of ACTH, and rapid transcription of steroidogenic genes, including StAR and MRAP. We also show that ultradian corticosterone secretion is further associated with rapid and transient transcription of nuclear receptors that regulate steroidogenic genes expression, including SF-1, Nur77, and Dax-1. By using a model of immunological stress we show that disruption of these dynamics leads to abnormal glucocorticoid secretion, as observed in disease and critical illness in both human and the rat. Finally, by using mathematical modelling we show that intra-adrenal negative-feedback mechanisms involving the activity of the glucocorticoid receptor appears to be an important factor in the dynamic regulation of these processes.