Oral drugs are successful because they are able to achieve the appropriate in vivo plasma concentrations such that they are efficacious and safe for a given dosing regimen. Critically, a compound's in vivo plasma concentration is a function of its molecular structure. Therefore, compound attrition may be reduced by focussing on estimated in vivo plasma concentration at the virtual or early drug design stage. Heuristic approaches have been used to develop criteria for human in vivo plasma concentrations based on 215 marketed oral drugs. By understanding pharmacokinetic species differences between human, dog and rat, human criteria can be translated into criteria for preclinical species. In human, the maximum to minimum plasma concentration has been revised to 7 and the free maximum plasma concentration is 100 nM; in dog, the criteria are 10-fold larger and 1.5-fold smaller, respectively, and in rat are 100-fold larger and 2.7-fold smaller, respectively.