The use of chemical food preservatives has allowed for longer product shelf lives, and reduced instances of microbial-derived food spoilage. The main United States regulatory agency responsible for evaluating safety of chemical additive in food is the Food and Drug Administration (FDA). It wasn’t until 1977 that the FDA approved the first chemical preservatives considered “safe” for food use. As of 2022, 45 years after the first FDA approval, very little work has been done to re-evaluate the safety and efficacy of these chemicals to better align with current scientific standards. This stagnancy is not an indicator that issues of safety and efficacy are completely solved or “known,” as further tests of low-dose, long-term exposure has not been explored. For many of the chemical preservatives found in food, we still do not have a clear picture of the molecular targets associated with each compound, or a description of primary and secondary effects on target food spoilage or safety organisms. Even further, it is possible that microbes have evolved new ways to overcome the environmental stresses caused by the repeated use of the same chemical preservatives. Thankfully, new technologies that focus more deeply on microbial responses to chemical additives have emerged over the past 20 years that could help to fill major gaps in knowledge concerning the mechanisms of action by which these chemical preservatives work. One such method that has been successfully applied to pharmacology is functional genomics, which uses genome-scale mutant collections to identify highly sensitive or less sensitive mutants after exposure to any environmental stressor. If applied to future chemical preservative evaluations, functional genomics could provide new insights and further reduce microbial-derived food spoilage and contamination. In this dissertation I a.) present a brief narrative concerning the history of chemical additives in food, b.) describe how chemical safety testing is currently performed, as well as how functional genomics could be specifically incorporated, c.) present research that supports the use of yeast as model organism for functional genomic testing of chemical food preservatives, and iv.) highlight the potential for “fingerprinting” the mechanisms of action at work for different chemical preservatives.