Stimulus control was established in rats trained to discriminate either 5-meth- oxy-N,N-dimethyltryptamine (3 mg/kg) or ( )-2,5-dimethoxy-4-methylamphetamine (0.56 mg/kg) from saline. Tests of antagonism of stimulus control were conducted using the 5-HT1A antagonists ( )-pindolol and WAY-100635, and the 5-HT2 receptor antagonist pirenperone. In rats trained with 5-MeO-DMT, pindolol and WAY-100635 both produced a significant degree of antagonism of stimulus control, but pirenperone was much less effective. Likewise, the full generalization of 5-MeO-DMT to the selective 5-HT1A agonist [ ]-8-hydroxy-dipropylaminotetralin was blocked by WAY-100635, but unaf- fected by pirenperone. In contrast, the partial generalization of 5-MeO-DMT to the 5-HT2 agonist DOM was completely an- tagonized by pirenperone, but was unaffected by WAY-100635. Similarly, in rats trained with ( )-DOM, pirenperone com- pletely blocked stimulus control, but WAY-100635 was inactive. The results obtained in rats trained with ( )-DOM and tested with 5-MeO-DMT were more complex. Although the intraperitoneal route had been used for both training drugs, a significant degree of generalization of ( )-DOM to 5-MeO-DMT was seen only when the latter drug was administered sub- cutaneously. Furthermore, when the previously effective dose of pirenperone was given in combination with 5-MeO-DMT (SC), complete suppression of responding resulted. However, the combination of pirenperone and WAY-100635 given prior to 5-MeO-DMT restored responding in ( )-DOM-trained rats, and provided evidence of antagonism of the partial substitu- tion of 5-MeO-DMT for ( )-DOM. The present data indicate that 5-MeO-DMT–induced stimulus control is mediated pri- marily by interactions with 5-HT1A receptors. In addition, however, the present findings suggest that 5-MeO-DMT induces a compound stimulus that includes an element mediated by interactions with a 5-HT2 receptors. The latter component is not es- sential for 5-MeO-DMT–induced stimulus control, but is revealed in animals tested or trained with a 5-HT2-selective agonist such as ( )-DOM. Based upon the present data, we conclude that 5-MeO-DMT differs from DOM with respect to the sero- tonergic element that mediates stimulus control in the rat, but that it shares with DOM a functionally significant interaction with 5-HT2 receptors.