Chronic exposure to elevated glucocorticoid levels is associated with obesity, insulin resistance, impaired glucose tolerance, hypertension and dyslipidaemia, manifest classically in Cushing's syndrome and with high-dose glucocorticoid therapy. However, cardiovascular events are also reportedly higher in patients with primary and secondary hypoadrenalism receiving 'replacement' glucocorticoid doses. This has been attributed to an inability to mimic accurately the diurnal rhythm of cortisol with current oral replacement therapy and subsequent glucocorticoid excess. Although development of delayed release oral preparations has sought to overcome this problem, there has been little attention on the ultradian rhythm of glucocorticoids and its relevance for replacement therapy and associated cardio-metabolic comorbidity. Endogenous glucocorticoids are released in a pulsatile manner, and this ultradian rhythm is important in maintaining homeostatic control through glucocorticoid-receptor (GR)-dependent transcription regulation that rapidly responds to circulating hormone levels. Constant glucocorticoid exposure can result in continuous transcription, aberrant mRNA accumulation and abnormal protein levels. GR regulation of transcription programmes is highly cell and tissue specific, binding to distinct genomic loci in different cellular contexts. GR also interacts with a large cohort of DNA-binding factors with cell-specific interactions. The relevance of kinetic patterns of GR-dependent gene expression in vivo is not yet fully elucidated. However, given that GR gene variants are associated with cardiovascular disease, it is possible that ultradian delivery of glucocorticoid replacement may become important, at least in selected patients. © 2014 John Wiley & Sons Ltd.