The economic case for fundamental changes that are required to ensure long term viability of the pharmaceutical industry demands a close look at which compounds are advanced into clinical development. This perspective will cover recent efforts that have had the greatest influence on defining the optimal range of physical properties of compounds that are intended to act as human therapeutic agents. Our focus will be on models and properties that are most amenable to change via synthetic design, are potentially fixable in the lead optimization process, and have the greatest impact on overall attrition in clinical development. In particular, we will examine the optimal physicochemical properties for oral absorption based on solubility, permeability, and a few easily computed parameters. Additionally, the fate of compounds that have entered clinical trials provides a compelling case for adhering to the defined properties ranges. Finally, emerging data suggests that there has been a shift in the leading causes of compound attrition, and attention should now be focused on building toxicological models to guide drug discovery efforts.