The experience of chronic stressors in early childhood, such as family poverty, neighborhood and school chaos, and family conflict have substantial negative consequences for life course physical and mental health, academic achievement, and ultimate social, educational, and economic attainment. With this proposal, we focus on neurobiological mechanisms that link chronic stress associated with family, neighborhood, and school disadvantage to impaired academic achievement. We hypothesize that the association between chronic stress and academic achievement is mediated by the effects of cortisol on executive functions. Executive functions are regulatory processes that support the acquisition of academic skills by allowing the learner to store information temporarily, adapt to task demands, and pay attention to relevant stimuli. Functional magnetic resonance imaging (fMRI) studies indicate that the child brain exhibits characteristic patterns of activation during executive functioning tasks. Many of these same regions have high concentrations of glucocorticoid receptors. Thus, stress-related disruptions in cortisol function are likely to affect the neural bases of executive functions. Cortisol is typically conceptualized s a mediator of the effects of environmental stress; however, genes also influence cortisol function. No previous study has comprehensively tested whether mechanisms underlying cortisol-achievement associations are purely environmental and whether, additionally or alternatively, cortisol is a physiological endophenotype that mediates genetic influences on executive functions and academic achievement. The proposed research will combine cutting-edge methods and technologies from endocrinology and neuroscience with well-developed methods from human ecology and behavioral genetics to explore the associations between chronic stress, cortisol, executive functions, and achievement. We will collect socioecological data, hair cortisol samples, executive function data, and school transcript achievement outcomes from a diverse and population-representative sample of 300 twins (150 pairs, 50% monozygotic) in grade 3, half of whom (N=150 twins from 75 pairs) will participate in fMRI scanning during performance of executive function tasks. This highly innovative and cross-disciplinary approach will allow us to: (1) Test the magnitude and shape of associations between hair cortisol and key study variables - socioecological stress, executive functions, and academic achievement; (2)Test a multivariate model of the mediating roles of cortisol and executive functions on the association between stress and achievement; and (3) Estimate the extent to which key pathways identified in the mediation model occur via genetic and/or environmental mechanisms.