The final Food and Drug Administration guidance on the safety testing of drug metabolites was published in February 2008. Discussions of the role and applications of this guidance were addressed at several public scientific meetings over the past year. One of the main differences between the draft and the finalized guidance is that in the latter, the human metabolite level was correlated to the parent drug level in plasma, whereas this parameter was considered in relationship to administered dose or total exposure in the draft guidance. The parent drug concentration in plasma has traditionally been the parameter commonly measured in animals during drug development and the one used to estimate drug clinical levels and to assess human risk. Moreover, circulating parent drug in general is the molecule with the intended therapeutic and pharmacologic effect. Therefore, it is appropriate to compare metabolite concentration to that of the parent drug. This report elaborates on this issue and supports other alternative rational and scientific approaches on the design of nonclinical studies that may be needed to test a human drug metabolite.