Adrenal insufficiency (AI), deficiency in the adrenal glucocorticoid cortisol, is rare: prevalence per million of the population is ~80 for Congenital Adrenal Hyperplasia (CAH), ~100 for Addison’s disease and ~200 for hypopituitarism. Treatment is to replace cortisol and first line treatment is replacement with hydrocortisone (pharmaceutical name for cortisol). Despite glucocorticoid replacement, patients with AI have an increased mortality and impaired quality of life. CAH patients have the additional problem that failure of cortisol negative feedback results in excessive ACTH secretion driving elevated adrenal androgens resulting in precocious puberty in children and infertility in adults. The poor health outcomes in AI primarily relate to inadequate or excessive glucocorticoid replacement and a failure to replace the normal circadian overnight rise in cortisol. This has driven the development of therapies to optimise glucocorticoid replacement. These include Alkindi, taste-masked hydrocortisone granules in capsules for opening, which provide age-appropriate dose titration for the growing child. Replacing the circadian rhythm of cortisol has been trialled with the continuous subcutaneous infusion of hydrocortisone and modified release formulations of hydrocortisone including Plenadren, a once daily preparation of hydrocortisone, and Efmody (Development name, Chronocort), a delayed-release hydrocortisone formulation that replaces the cortisol circadian rhythm. Chronocort improved control of CAH in 80% of patients on an adrenal replacement dose of hydrocortisone which was associated with patient reported benefit including restoration of menses and pregnancies. A recently completed double blind study has compared Chronocort with Plenadren in primary AI showing Chronocort provides more physiological levels of cortisol and analysis of QoL is awaited. An alternative approach in CAH is to reduce ACTH secretion or biological action using either a Corticotrophin Releasing Factor type 1 receptor (CRF1) antagonist such as Crinecerfont, or an ACTH receptor antagonist or inhibitory ACTH antibodies. A phase 3 study with Crinecerfont has demonstrated that treatment can reduce androgen biomarkers and allow reduction in the glucocorticoid replacement dose. Finally, gene therapy studies are in the early stages and there is a trial for gene therapy to provide functional copies of the 21-hydroxylase-encoding gene using an adeno-associated virus. Studies are now required to examine whether improving glucocorticoid replacement can reduce the morbidity and mortality seen in patients with AI.