To determine whether serotonin is involved in the regulation of renin secretion in unanesthetized rats, plasma renin activity was measured in animals treated with the serotonin-depleting drugs p-chlorophenylalanine and 5,7-dihydroxytryptamine, with the serotonin releasing drug p-chloroamphetamine and with the serotonin agonist quipazine. Plasma corticosterone was also measured. p-Chlorophenylalanine decreased plasma renin activity and p-chlorophenylalanine plus 5-hydroxytryptophan increased plasma renin activity. Plasma renin activity was also reduced in rats that had received intraventricular 5,7-dihydroxytryptamine after pretreatment with desmethylimipramine. p-Chlorophenylalanine and 5,7-dihydroxytryptamine did not change plasma corticosterone concentration. p-Chloroamphetamine and quipazine produced dose-dependent increases in plasma renin activity and plasma corticosterone. The increase in plasma renin activity produce by quipazine was more rapid than that produced by p-chloroamphetamine. The effects of p-chloroamphetamine on plasma renin activity and plasma corticosterone were prevented by prior administration of p-chlorophenylalanine. The renin stimulating effect of p-chloroamphetamine was unaffected by adrenalectomy. L-Tryptophan failed to increase plasma renin activity. The data support the hypothesis that in rats release of serotonin within the central nervous system increases renin secretion and corticosterone secretion and that the increase in renin is independent of the increase in corticosterone.