Social isolation is a potent predictor of poor health, mortality, and dementia risk. A great deal of research across national contexts provides causal evidence for these linkages and identifies key explanatory mechanisms through which isolation affects health. Research on social isolation recognizes that some people are more likely than others to be isolated, but over the past several decades, researchers have focused primarily on the consequences of isolation for health rather than a systematic assessment of the social conditions that foster isolation over the life course. In this article, we review the available evidence on inequities in social isolation and develop a conceptual framework to guide future research on structural systems that fuel social isolation over the life course. Future work in this area has the potential to identify root causes of inequality in social isolation, as well as targeted policy levers to reduce isolation in vulnerable populations.