Primary adrenal insufficiency (AI) is often a consequence of autoimmune destruction of the adrenal cortex, but a number of other causes have been reported, including genetic diseases, haemorrhage, infections, infiltration by tumour or metastasis, and medication. AI is rare with reported prevalence at 1020 per 100 000 inhabitants. Before replacement therapy with corticosteroids became available, AD was invariably fatal. Accessibility to hydrocortisone and fludrocortisone was a revolution and offered patients near normal life expectancies, although mortality has been reported to be increased in some populations. Recent years have however revealed that despite state-of-the art treatment, many patients experience reduced health-related quality of life (HRQoL) and reduced ability to participate in the work force. A leading hypothesis has been that the unphysiological replacement regimens we offer is a major factor to explain these limitations. This has spurred development of alternative replacement strategies including extended release medication and subcutaneous administration of hydrocortisone by infusion. Despite these new tools, providing personalized treatment in AI is still a major challenge as we currently lack biomarkers to guide replacement therapy to the individual patient. Evolving evidence point to the fact that some patients retain the ability to produce significant amounts of corticosteroids despite many years of autoimmune AI. These patients might represent a subgroup with better HRQoL, fewer adrenal crises and could be subjects for regenerative treatment to partly or fully restore adrenocortical function. Taken together these novel developments is about bring care for AI patients into the era of personalized medicine.