The 2016 Frank Lautenberg Chemical Safety for the 21st Century Act (Lautenberg TSCA) amended the 1976 Toxic Substances Control Act (TSCA) to mandate protection of susceptible and highly exposed populations. Program implementation entails a myriad of choices that can lead to different degrees of public health protections. Well-documented exposures to multiple industrial chemicals occur from air, soil, water, food, and products in our workplaces, schools, and homes. Many hazardous chemicals are associated with or known to cause health risks; for other industrial chemicals, no data exist to confirm their safety because of flaws in 1976 TSCA. Under the 2016 Lautenberg amendments, the United States Environmental Protection Agency (EPA) must evaluate chemicals against risk-based safety standards under enforceable deadlines, with an explicit mandate to identify and assess risks to susceptible and highly exposed populations. Effective public health protection requires EPA to implement the Lautenberg TSCA requirements by incorporating intrinsic and extrinsic factors that affect susceptibility, adequately assessing exposure among vulnerable groups, and accurately identifying highly exposed groups. We recommend key scientific and risk assessment principles to inform health-protective chemical policy such as consideration of aggregate exposures from all pathways and, when data are lacking, the use of health-protective defaults.