The term social determinants of health (SDOH) is often used to refer to any nonmedical factors influencing health, including health-related knowledge, attitudes, beliefs, or behaviors (e.g., smoking); however, SDOH also include "upstream" factors, such as social disadvantage, risk exposure, and social inequities that play a fundamental causal role in poor health outcomes — and thus represent important opportunities for improving health and reducing health disparities. This paper describes and categorizes three types of approaches used to examine upstream SDOH. Social disadvantage approaches focus on the link between health and neighborhood conditions, working conditions, education, income and wealth, and race/ethnicity and racism; a potential causal link is the role of stress related to coping with these factors. Life course approaches focus on the link between health and critical or sensitive periods in exposure to risk (adverse childhood experiences, intergenerational transfer of advantage) as well as cumulative exposures; the potential causal link here may derive from the effect of social status on the regulation of genes controlling physiologic functions (e.g., immune functioning). Health equity approaches consider the link between health and social inequities stemming from socio-demographic factors, such as class, immigration status, gender, sexual orientation, and disability status; social capital can serve to moderate or mediate the effects of these factors. The paper identifies several challenges to understanding upstream SDOH, including the long and complex causal pathways linking these factors with health, multiple intervening factors, limited ability to study these factors using randomized experiments, single-disease-focused research funding, and limited understanding of community buffers that can mitigate the effects of SDOH.