The photochemical fates of the histamine H2-receptor antagonists cimetidine and ranitidine were studied. Each of the two environmentally relevant pharmaceuticals displayed high rates of reaction with both singlet oxygen (1O2, O2(1Δg)) and hydroxyl radical (.OH), two transient oxidants formed in sunlit natural waters. For cimetidine, the bimolecular rate constant for reaction with .OH in water is 6.5 ± 0.5 × 109 M-1 s-1. Over the pH range 4-10, cimetidine reacts with 1O2 with bimolecular rate constants ranging from 3.3 ± 0.3 × 106 M-1 s-1 at low pH to 2.5 ± 0.2 × 108 M-1 s-1 in alkaline solutions. The bimolecular rate constants for ranitidine reacting with 102 in water ranges from 1.6 ± 0.2 × 107 M-1 s-1 at pH 6-6.4 ± 0.2 × 107 M-1 s-1 at pH 10. Reaction of ranitidine hydrochloride with .OH proceeds with a rate constant of 1.5 ± 0.2 × 1010 M-1 s-1. Ranitidine was also degraded in direct photolysis experiments with a half-life of 35 min under noon summertime sunlight at 45 ° latitude, while cimetidine was shown to be resistant to direct photolysis. The results of these experiments, combined with the expected steady-state near surface concentrations of 1O2 and .OH, indicate that photooxidation mediated by 1O2 is the likely degradation pathway for cimetidine in most natural waters, and photodegradation by direct photolysis is expected to be the major pathway for ranitidine, with some degradation caused by 1O2. These predictions were verified in studies using Mississippi River water. Model compounds were analyzed by laser flash photolysis experiments to assess which functionalities within ranitidine and cimetidine are most susceptible to singlet-oxygenation and direct photolysis. The heterocyclic moieties of the pharmaceuticals were clearly implicated as the sites of reaction with 1O2, as evidenced by the high relative rate constants of the furan and imidazole models. The nitroacetamidine portion of ranitidine has been shown to be the moiety active in direct photolysis.