1. Men are generally at greater risk for cardiovascular disease than are women, particularly with regard to enhanced progression of hypertension and loss of renal function. Despite these gender differences in the progression of hypertension and renal disease in humans and animals, the mechanisms responsible are unknown. 2. Castration in males has been shown to slow the progression of hypertension and ameliorate the loss in renal function. When serum testosterone was measured in the developing male spontaneously hypertensive rat (SHR), the peak serum testosterone level at 12 weeks coincided with the time when differences in systolic blood pressure could be measured between intact male SHR and females or castrated male SHR. Ovariectomy does not affect blood pressure in female SHR but testosterone treatment of ovariectomized females for 5 weeks results in exacerbation of hypertension almost to the level found in intact male SHR. These data strongly suggest a role for androgens in mediating the gender differences in hypertension. 3. The mechanisms by which androgens could increase blood pressure are not known. We have recently shown that, at comparable renal perfusion pressures, there is a hypertensive shift in the pressure-natriuresis relationship in male SHR compared with females or castrated male SHR. Testosterone treatment of ovariectomized female SHR also causes a rightward shift in the pressure-natriuresis relationship. 4. We hypothesize that androgens increase arterial pressure by causing a hypertensive shift in the pressure-natriuresis relationship, either by having a direct effect to increase proximal tubular reabsorption or by activation of the renin-angiotensin system. We also hypothesize that the enhanced proximal tubular reabsorption leads to a tubuloglomerular feedback-mediated afferent vasodilation, which, in combination with the increase in arterial pressure, results in glomerular hypertension and renal injury.