The development of self-regulation is believed to play a crucial role in predicting later psychopathology and is believed to begin in early childhood. The early postpartum period is particularly important in laying the groundwork for later self-regulation as infants' dispositional traits interact with caregivers' co-regulatory behaviors to produce the earliest forms of self-regulation. Moreover, although emerging literature suggests that infants' exposure to maternal stress even before birth may be integral in determining children's self-regulatory capacities, the complex pathways that characterize these developmental processes remain unclear. The current study considers the complex, transactional processes in a high-risk, Mexican American sample. Data were collected from 305 Mexican American infants and their mothers during prenatal, 6- and 12-week home interviews. Mother self-reports of stress were obtained prenatally between 34-37 weeks gestation. Mother reports of infant temperamental negativity and surgency were obtained at 6-weeks as were observed global ratings of maternal sensitivity during a structured peek-a-boo task. Microcoded ratings of infants' engagement orienting and self-comforting behaviors were obtained during the 12-week peek-a-boo task. Study findings suggest that self-comforting and orienting behaviors help to modulate infants' experiences of distress, and also that prenatal stress influences infants' engagement in each of those regulatory behaviors, both directly by influence tendencies to engage in orienting behaviors and indirectly by programming higher levels of infant negativity and surgency, both of which may confer risk for later regulatory disadvantage. Advancing our understandings about the nature of these developmental pathways could have significant implications for targets of early intervention in this high-risk population.