The effects of four xanthines (theophylline, 8-phenyltheophylline, isobutylmethylxanthine (IBMX), and 7-benzyl-IBMX) were studied in the hippocampal slice in vitro. These agents increased the excitability of this preparation with 8-phenyltheophylline being the most potent, 7-benzyl-IBMX the least potent, and theophylline and IBMX having intermediate potencies. A similar rank order was observed in terms of the potencies of these xanthines in antagonizing a) electrophysiological responses to adenosine, and b) adenosine-stimulated cyclic AMP formation. These results indicate that the excitatory actions of xanthines in the vivo hippocampus can be most easily explained on the basis of their ability to block adenosine's actions; the CNS excitatory actions of these drugs in vivo may depend upon a similar mechanism of action.