Abstract-Approximately 10% of patients with hypertension have a high ratio of aldosterone to renin, but the reason for this and the relationships among low-renin essential hypertension, elevation of the ratio, and true primary aldosteronism are unclear. We have previously reported that a polymorphism of the gene (C-to-T conversion at position Ϫ344) encoding aldosterone synthase is associated with hypertension, particularly in patients with a high ratio. However, the most consistent association with this variant is a relative impairment of adrenal 11-hydroxylation. In this review, we propose that altered conversion of deoxycortisol to cortisol leads to a subtle, chronic increase in adrenocortrophin drive to the adrenal cortex, with eventual development of hyperplasia. In combination with other genetic or environmental factors (such as dietary sodium intake), we suggest that this might be responsible for the long-term development of a resetting of the aldosterone response to angiotensin II, giving rise to the phenotype of hypertension with a raised ratio.In some subjects, this may progress further to true primary aldosteronism with a dominant adrenal nodule. Thus, there may be a genetically influenced continuum from hypertension with a normal ratio, through hypertension with a raised ratio, and primary aldosteronism. Key Words: hypertension, mineralocorticoid Ⅲ adrenal gland Ⅲ aldosterone Ⅲ adrenocorticotropic hormone Despite many years of research, the pathophysiology of essential hypertension remains uncertain, and it seems likely that no single cause exists. This may best be appreciated by considering the lessons from rodent models of hypertension. Here, selective inbreeding has generated strains that develop high blood pressure through a range of distinct mechanisms. For example, the role of adducin in the Milan hypertensive rat contrasts with the involvement of corticosteroids in the Dahl salt-sensitive strain; in each instance, distinct genetic loci can be identified to account for the development of high blood pressure. 1,2 Nevertheless, in both types of hypertension, the phenotype is exacerbated by sodium loading, and only careful study of the intermediate phenotype (in this instance, measurement of adrenal steroid production) allows the pathogenesis to be understood. The same argument can be applied to human hypertension, and it would be naïve to anticipate that the same underlying mechanism was present in all patients with high blood pressure. However, careful study of subgroups might identify common mechanisms that account for the rise in pressure and offer guidance to the best therapeutic option. In this regard, the contribution of adrenal steroids deserves careful review. At a gross level, of course, corticosteroids clearly do have an important role in the development of hypertension. Patients with Addison's disease are hypotensive, 3 glucocorticoid excess in patients with Cushing's syndrome is associated with high blood pressure, 4 and the role of a major excess of aldosterone in classic Conn's synd...