We report on a new preclinical drug optimization strategy that measures drug candidates’ binding affinity with human serum albumin (HSA) as an assessment of increasing or decreasing serum T1/2. Three common scaffolds were used as drug prototypes. Common polar and nonpolar substituents attached to the scaffolds have been identified as opportunities for increasing or decreasing the HSA binding affinity. This approach of adjusting HSA binding could be proactively established for preclinical drug candidates by appending functionality to sites on the drug scaffold not involved in biological target interactions. This strategy complements other medicinal chemistry efforts to identify longer or shorter human dosing regimens.