After a brief review of a number of issues related to the enzymatic hydrolysis of carboxylic esters, scuh as interspecies variability, mechanism, stereospecificity, and activation energy, and after and overview of relevant aspects related to the quantitative modeling of steric effects, the results of a recently developed quantitative structure-metabolism relationship model are discussed. They were obtained for in vitro human blood enzymatic hydrolysis of noncongener esters by introduction of the inaccessible solid angle as a novel measure of steric hindrance.