Drugs that enhance brain serotonin function (direct agonists, serotonin uptake inhibitors and serotonin releasers) increase serum corticosterone concentration in rats, and in many cases ACTH has been shown to be similarly increased. At least two distinct serotonin receptor subtypes can mediate this effect. One is the 5-HT1A receptor, and the other seems to be a 5-HT2A receptor. Possibly, the 5-HT2C receptor or other receptors can also mediate these effects. The increase in serum corticosterone seems to be one useful marker in characterizing drug effects on serotonergic function. Much needs to be learned about the physiological importance and roles of this serotonergic influence on pituitary-adrenocortical function. Some studies have suggested it may be important in the diurnal rhythmicity of glucocorticoid secretion and perhaps in some stress effects. Serotonergic activation can also increase plasma levels of ACTH and cortisol in humans. Although the effects in humans are less well characterized than in rats, they seem to be useful as a way of probing brain serotonergic function in disease or after drug treatment. As more drugs that act selectively on a single receptor subtype become available for use in humans, more precise information about particular receptor subtypes should be attainable.