Neurobiological models propose an evolutionary, vertical-integrative perspective on emotion and behavior regulation, which postulates that regulatory functions are processed along three core brain systems: the brainstem, limbic, and cortical systems. To date, few developmental studies applied these models to research on prenatal and perinatal risk. We propose a conceptual model that incorporates three integrated levels of observations for the study of early risk: (a) brainstem-related physiological regulation of cyclic processes and sensory integration, e.g., vagal regulation, circadian rhythms; (b) emotion and attention regulation capacities that draw on the integration of brainstem and limbic systems; and (c) higher-level outcomes that draw on the intactness of brainstem and limbic networks, including socio-emotional self-regulation, inhibitory control, and cognitive processing. We discuss implications of the model for the development of regulatory capacities during the prenatal and early postnatal stages in infants born with specific perinatal risk. We underscore the importance of assessing sub-cortical and brainstem systems and the longitudinal effects of transitory brainstem dysfunction on physiological homeostasis, motivation, arousal-modulated attention, stress reactivity, and mother-infant co-regulation. The assessment of brainstem dysfunction can be conducted during hospitalization and may help detect infants at risk for the development of self-regulatory deficits at the first weeks of life.