Social Determinants of Health (SDOH) consider social, political, and economic factors that contribute to health disparities in patients and populations. The most common health-related SDOH exposures are food and housing insecurity, financial instability, transportation needs, low levels of education, and psychosocial stress. These domains describe risks that can impact health outcomes more than health care. Epidemiologic and translational research demonstrates that SDOH factors represent exposures that predict harm and impact the health of individuals. International and national guidelines urge health professionals to address SDOH in clinical practice and public health. The further implementation of these recommendations into basic and translational research, however, is lagging. Herein, we consider a precision health framework to describe how SDOH contributes to the exposome and exacerbates physiologic pathways that lead to chronic disease. SDOH factors are associated with various forms of stressors that impact physiological processes through epigenetic, inflammatory, and redox regulation. Many SDOH exposures may add to or potentiate the pathologic effects of additional environmental exposures. This overview aims to inform basic life science and translational researchers about SDOH exposures that can confound associations between classic biomedical determinants of disease and health outcomes. To advance the study of toxicology through either qualitative or quantitative assessment of exposures to chemical and biological substances, a more complete environmental evaluation should include SDOH exposures. We discuss common approaches to measure SDOH factors at individual and population levels and review the associations between SDOH risk factors and physiologic mechanisms that influence chronic disease. We provide clinical and policy-based motivation to encourage researchers to consider the impact of SDOH exposures on study results and data interpretation. With valid measures of SDOH factors incorporated into study design and analyses, future toxicological research may contribute to an evidence base that can better inform prevention and treatment options, to improve equitable clinical care and population health.