This article proposes several conceptual perspectives designed to advance our understanding of the material and experiential conditions contributing to persistent disparities in rates of morbidity and mortality among groups unequal in their social and economic statuses. An underlying assumption is that these disparities, which are in clear evidence at mid- and late life, may be anchored to earlier circumstances of the life course. Of particular interest are those circumstances resulting in people with the least privileged statuses having the greatest chances of exposure to health-related stressors. Among the stressors closely linked to status and status attainment are those that continue or are repeated across the life course, such as enduring economic strain and discriminatory experiences. Also taking a long-range toll on health are circumstances of stress proliferation, a process that places people exposed to a serious adversity at risk for later exposure to additional adversities. We suggest that this process can be observed in instances of trauma, in early out-of-sequence transitions, and in the case of undesired changes that disrupt behaviors and relationships in established roles. Effective effort to close the systemic health gaps must recognize their structural underpinnings.