Current therapy with immediate-release hydrocortisone is the most commonly used regimen for replacement in patients with primary and secondary adrenal insufficiency. However, conventional hydrocortisone cannot provide the physiological rhythm of cortisol release. Physicians have used fixed twice- or thrice-daily doses, but these regimens inevitably result in temporary over- or under-replacement. Patients with adrenal insufficiency, although on treatment, have a poor quality of life and an increased mortality. Optimization of current treatment has been attempted with thrice-daily, weight-related dosing, but this still fails to simulate the normal diurnal rhythm of cortisol. Recent research has investigated circadian hydrocortisone therapy imitating the physiological cortisol rhythm. Proof-of-concept studies using hydrocortisone infusions predict improvements in biochemical control and quality of life. Now delayed and sustained release oral formulations of hydrocortisone are being developed, and these offer a more practical and effective solution for patients with adrenal insufficiency and congenital adrenal hyperplasia.