Preterm birth and infant mortality disproportionately affect African American families compared to White families. More than 18% of African American infants are born preterm (< 37 weeks' gestation) compared to just less than 12% of White infants. Consequently, African American infants are twice as likely to die in their first year of life as White infants. Differences in socioeconomic status, prenatal care usage, and behavioral characteristics fail to explain the disparity in preterm birth between African Americans and Whites. Epidemiologic data support a life-course conceptual model for African American women's pregnancy disadvantage. Life-course factors influence pregnancy outcomes through two proposed mechanisms: early-life (fetal) programming of reproductive potential and cumulative wear and tear (weathering). The biologic mechanisms behind this theory are poorly understood. In this commentary, we argue that epigenetic inquiry represents the next frontier in investigating the mechanisms underlying racial disparities in birth outcome. We propose this with the hope that these discoveries will lead to opportunities for interventions and ultimate improvements in birth outcomes.