The realization that primary aldosteronism (PA) is a much more common cause of hypertension than previously thought, and that aldosterone excess has adverse effects that are at least partly independent of blood pressure, have been the main driving forces for a renaissance in clinical and research interest in PA. This has included numerous studies and recent new insights into its genetic bases and the downstream molecular mechanisms by which these mutations result in PA. Elucidation in the early 1990’s of the inherited, ACTH-regulated hybrid CYP11B1/CYP11B2 gene mutation causing familial hyperaldosteronism type I (FH-I) provided a full explanation of the ACTH-dependent (and therefore glucocorticoid-remediable) overproduction of aldosterone and “hybrid” steroids (18-hydroxy- and 18-oxo-cortisol) that characterizes this rare familial form of PA, and led to more streamlined, genetic methods of diagnosis. During the past 2 years, several groups have described the presence of somatic mutations within KCNJ5 (encoding a potassium channel) in approximately 40% of aldosterone-producing adenomas (APAs). Compared with APAs not containing mutations, somatic KCNJ5 mutations appear to be associated with younger age, female gender, more severe PA, lack of responsiveness of plasma aldosterone to upright posture and zona fasciculata histology. Of five so far described, G151R and L168R are by far the most common. KCNJ5 mutations lead to reduced K⁺/Na⁺ channel selectivity and Na⁺ influx, predisposing to cell membrane depolarization, increased calcium influx, increased expression of genes promoting aldosterone synthesis and increased aldosterone production by adrenocortical cells. How they lead to adrenal cell proliferation and tumor development is less well understood. Much rarer germline KCNJ5 mutations cause bilateral, early-onset familial PA with variable severity (ranging from mild PA and normal adrenal morphology on adrenal imaging to severe PA with markedly elevated hybrid steroid levels and massively enlarged adrenals due to diffuse hyplerplasia of zona fasciculata) and apparent genotype:phenotype correlations. Very recently, a report has described somatic mutations in ATP1A1 (encodes Na⁺/K⁺ ATPase) and ATP2B3 (encodes Ca²⁺ ATPase) in a small proportion (5.2 and 1.6% respectively) of APAs studied. To date no germline mutations in these two genes have been found in patients with PA (either apparently sporadic or familial). COS cells with ATP1A1 mutations showed loss of Na⁺/K⁺ ATPase pump activity (causing Na⁺ to be retained in cells) and markedly reduced K⁺ affinity, and adrenal adenoma cells bearing ATP1A1 or ATP2B3 mutations showed evidence of depolarization. Collectively, these findings have shed considerable light on the pathophysiology of PA with the potential to lead to new diagnostic approaches and treatments.