© 2016 This review article addresses the concept of the social determinants of health (SDH), selected theories, and its application in studies of chronic disease. Once ignored or regarded only as distant or secondary influences on health and disease, social determinants have been increasingly acknowledged as fundamental causes of health afflictions. For the purposes of this discussion, SDH refers to SDH variables directly relevant to chronic diseases and, in some circumstances, obesity, in the research agenda of the Mid-South Transdisciplinary Collaborative Center for Health Disparities Research. The health effects of SDH are initially discussed with respect to smoking and the social gradient in mortality. Next, four leading SDH theories—life course, fundamental cause, social capital, and health lifestyle theory—are reviewed with supporting studies. The article concludes with an examination of neighborhood disadvantage, social networks, and perceived discrimination in SDH research.