For decades, racial residential segregation has been observed to vary with health outcomes for African Americans, although only recently has interest increased in the public health literature. Utilizing a systematic review of the health and social science literature, the authors consider the segregation-health association through the lens of 4 questions of interest to epidemiologists: How is segregation best measured? Is the segregation-health association socially or biologically plausible? What evidence is there of segregation-health associations? Is segregation a modifiable risk factor? Thirty-nine identified studies test an association between segregation and health outcomes. The health effects of segregation are relatively consistent, but complex. Isolation segregation is associated with poor pregnancy outcomes and increased mortality for blacks, but several studies report health-protective effects of living in clustered black neighborhoods net of social and economic isolation. The majority of reviewed studies are cross-sectional and use coarse measures of segregation. Future work should extend recent developments in measuring and conceptualizing segregation in a multilevel framework, build upon the findings and challenges in the neighborhood-effects literature, and utilize longitudinal data sources to illuminate opportunities for public health action to reduce racial disparities in disease.