The notion of test method validation, when applied to in vitro models, has been subjected to standards, practices, and regulatory mandates that may represent significant barriers to the development of new methods based on target toxicological pathways, mode of action, and mechanistic endpoints. Currently, there is an expectation that toxicity test methods used for regulatory purposes must be formally validated by a legislated body. In this manuscript, we review the genesis of current formal validation programs, their purpose, their justification for future need, and an examination of the scientific process as the driving force. With the collision of three major international events in the scientific and regulatory communities (viz. EU Cosmetic Directive, EU REACH legislation, and the NRC publication, Toxicity Testing in the 21st Century: A Vision and a Strategy), there may be a need for a shift in the current validation paradigm. Further, test method validity may be recognized by the appropriate authorities when specific criteria and the fundamental precepts of reliability and reproducibility have been adequately met.