The disposition of caffeine and its metabolites was studied in six healthy subjects by use of sensitive and specific assays. The primary degradation of caffeine in man was found to be N-demethylation and/or ring oxidation to theophylline, paraxanthine, theobromine and 1,3,7-trimethyluric acid. These compounds were further degraded to dimethylated uric acids, monomethylxanthines and monomethyluric acids. About 3 and 6% of the drug was converted to theophylline and theobromine, respectively. The elimination of paraxanthine after its formation did not follow linear kinetics. A large urine recovery of 1-methylxanthine after caffeine administration in comparison with the amount recovered after administration of theophylline suggests an inhibitory effect on the degradation of this metabolite by either caffeine itself or another metabolite of caffeine. Caffeine and its primary metabolites, dimethylxanthines, were extensively reabsorbed in the renal tubule. Their renal clearances were highly urine flow-dependent and their urinary excretion varied with urine output during the study. About 70% of the dose was recovered in the urine. Postulated degradation pathways of caffeine are discussed.