Nonselective oxidation of organic chemicals during TiO2 photocatalytic water treatment significantly prohibits decomposition of toxic target contaminants, particularly in the presence of naturally abundant less toxic natural organic matter (NOM). To minimize the adverse effect of NOM, the authors have investigated physical size exclusion of large NOM onto mesoporous TiO2 photocatalysts, which allows small target contaminants to selectively access the porous structure for subsequent chemical reaction. Various treatment scenarios tested with different targets (ibuprofen, microcystin-LR) and competitors (humic acid, polyethylene glycol), and a series of mesoporous TiO2 materials proved the size exclusion mechanism. Discussion was made on the impact of the porous structure of TiO2 on selectivity and reactivity, considering size difference among targets < TiO2 pores < competitors as well as mass transfer limitation of even a target to small pores. This simple approach would greatly improve the photocatalytic treatment of toxic chemicals in water containing NOM.