High numbers of serotonin transporter (SERT) binding sites and high serotonin (5-HT) content are expressed in the adrenal medulla of wild-type (SERT+/+) mice. Acute restraint stress increases adrenomedullary 5-HT, norepinephrine (NE) and epinephrine (E) release, adrenomedullary tyrosine hydroxylase (TH) mRNA, and angiotensin II AT<sub>2</sub> receptor expression. There are no alterations in adrenal catecholamine content during restraint. In littermate SERT–/– mice, which do not express SERT binding sites, the basal adrenomedullary 5-HT content is significantly reduced and does not increase after stress. The stress-induced increase in plasma E is higher in SERT–/– than in SERT+/+ animals. In SERT–/– mice, the stress-induced increase in expression of TH mRNA does not occur, and as a consequence, adrenal E content decreases, and adrenal E and NE content are lower than that of SERT+/+ mice during restraint. In addition, instead of increased expression, stress induces a profound decrease in the number of adrenomedullary AT<sub>2</sub> receptors in SERT–/– mice. Our results indicate that SERT is necessary for the stress-induced increase in adrenomedullary catecholamine synthesis and AT<sub>2</sub> receptor expression. These data further indicate a close relationship between the adrenomedullary 5-HT and angiotensin II systems, and an important role of adrenomedullary AT<sub>2</sub> receptors in catecholamine synthesis and release during stress.