The stimulus properties of caffeine were studied in separate groups of rats trained to discriminate between i.p. injections of saline and either 10 or 30 mg/kg of caffeine in a discrete-trial avoidance paradigm. Stimulus control of behavior (i.e., reliable completion of at least 18 of 20 trials on the appropriate choice lever after injection of saline or caffeine) was established in an average of 50 to 52 sessions. Novel drugs were tested over a range of doses for generalization to one (10 mg/kg) or both doses of caffeine. The methylxanthine derivatives, theophylline, theobromine, 1,7-dimethylxanthine, 3-isobutyl-l-methylxanthine, 8-phenyltheophylline and 8-chlorotheophylline, were generalized to caffeine partially or not at all. Of the nonxanthine drugs, apomorphine, clonidine and picrotoxin occasioned responding only on the saline-appropriate choice lever, d-amphetamine and ephedrine generalized partially, and cocaine and methylphenidate generalized with caffeine completely, as did 2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine an alpha-1 adrenergic receptor agonist. The discriminative effects of 10 mg/kg of caffeine were blocked dose-dependently and completely by alpha adrenergic receptor blocking drugs (phentolamine, prazosin and yohimbine) and were blocked partially by propranolol and by drugs having behavioral depressant properties (diazepam, pentobarbital and the adenosine analogs, R-(-)-N6-(2-phenylisopropyl)adenosine, cyclohexyladenosine, 2-chloroadenosine). The blockade by phentolamine could be surmounted by increasing the dose of caffeine, the partial blockade by diazepam and 2-chloroadenosine could not. Alpha adrenergic receptor blocking drugs also antagonized the caffeine-like discriminative effects of methylphenidate and 2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine. The discriminative stimulus effects of caffeine in the rat appear to be mediated in part by alpha adrenergic mechanisms.