Phosphate diester hydrolysis is strongly accelerated, by a factor of 104, in the presence of artificial enzymes especially designed in the light of spatiotemporal concepts, anchoring imidazoles in a pillar[5]arene matrix. Host:guest complexes cleave the aryl phosphodiesters via nucleophilic attack of the properly placed imidazole moieties with the release of 2,4-dinitrophenolate and the formation of unstable phosphoroamidates that regenerate the catalyst and 2,4-dinitrophenyl phosphate. Comparison of the reactivity of P5IMD with that of imidazole shows a 270-fold increase. Asymmetrical diesters allow the formation of two different docking structures of the host:guest complex, with just one being reactive and allowing selectivity increases of 102-fold, compared with the reaction in bulk water of the same asymmetrical diesters.