Rats were trained to discriminate methylxanthines from saline under a two-lever concurrent variable ratio schedule of reinforcement. One group was trained to discriminate between saline and 32 mg/kg caffeine. A second group was trained to discriminate between 56 mg/kg theophylline and saline. Rats reliably discriminated between saline and the training methylxanthine, displaying graded generalization curves across training-drug doses. Caffeine-trained rats demonstrated caffeine-appropriate responding when tested with theophylline, paraxanthine, and 3-methylxanthine. Theobromine failed to generalize to the caffeine cue at test doses up to 75 g/kg. In contrast to the caffeine group, rats trained to discriminate theophylline from saline were less sensitive (higher ED50) to the effects of caffeine and paraxanthine test doses. Only partial generalization to the theophylline cue occurred at paraxanthine doses up to 100 mg/kg. Based upon these data, it is suggested that the underlying substrate(s) for the caffeine cue is in some respects different from the substrate(s) for the theophylline cue.