Experiments in vitro and observation made in humans suggest that some unesterified fatty acids (FA) participate, as inhibitors, in the regulation of aldosterone secretion. Removal of FA from adrenal glomerulosa cells with albumin increases the responses to angiotensin II (AII) and dibutyryl cyclic AMP. Micromolar concentrations of some FA including arachidonic, oleic, linoleic, eicosapentaenoic, and docosahexaenoic inhibit aldosterone secretion by adrenal glomerulosa cells. Inhibition is specific--some acids like stearic are inactive, and the adrenal fasciculata is relatively resistant to inhibition. Oleic acid rapidly and reversibly inhibits aldosterone secretion by perfused dog adrenals. Observations in vivo suggest a reciprocal relationship between plasma levels of FA and aldosterone: insulin infusion into dogs lowers plasma FA and increases adrenal responsiveness to All; salt infusions into humans increase plasma FA as aldosterone falls; plasma FA are low in low-renin essential hypertension where adrenal responsiveness to All is high; plasma FA are inversely correlated with ratios of aldosterone to renin in black hypertensives; and plasma FA are high in some seriously ill patients whose aldosterone levels are inexplicably low. All receptors and the final step of aldosterone biosynthesis, oxidation at the 18 position, are the adrenal sites most sensitive to FA. Insulin's antinatriuresis may be mediated in part by its ability to lower plasma FA and thereby enhance adrenal response to secretagogues.