Efforts to personalize mental health and substance use prevention programs with underserved, impoverished racial minority youth require an understanding of the social environment risk factors that become biologically embedded to shape risk for poor health trajectories. Among African American (AA) youth from impoverished communities, exposure to violence, racial discrimination, poor neighborhood conditions, and stressful life events all impact risk for emotional and behavioral health problems, including symptoms of anxiety and depression, conduct/aggression problems, and substance use. Protective features of the neighborhood environment, however, can partially mitigate these risks. The biological processes by which stressors come to increase the risk for poor emotional/behavioral health is not well understood but likely involve changes in epigenetically-related processes including DNA methylation and telomere length (TL). The present study utilizes a well-characterized sample of 537 AA youth from high-poverty neighborhoods, among whom extensive assessments of life experiences, neighborhood environment, behavioral phenotyping, and genome- wide genetic polymorphisms have already been conducted. Utilizing a variety of cutting-edge methodologies spanning behavioral sciences and molecular and statistical genetics, we will examine genome-wide DNA methylation and TL as biological mediators of stress effects on emotional/behavioral health among impoverished AA youth. We also test for the moderating role of resilience-enhancing protective factors, sex, and genotype, all of which have been understudied in relation to methylation and TL. We propose to: (1) determine whether environmental stressors, including racial discrimination, exposure to violence, and neighborhood ecology are associated with DNA methylation and TL, reflective of a biological embedding of stress; (2) examine stress-linked variations in methylation and TL as mediators of stress effects on emotional/behavioral health; (3) identify social environment protective factors, including neighborhood factors, that could potentially buffer impacts of stress on health outcomes, and test for sex differences; (4) explore the role of genotype as a contributing factor to the relations between environmental stress, methylation, TL, and emotional/behavioral health. This research is innovative for its inclusion of both individual and neighborhood- level predictors, both risk and protective factors, and both social environment and genotype among a difficult- to-reach population of impoverished AA youth. Identifying stressors and resilience-enhancing protective factors with the strongest links to biological changes and behavioral functioning will aid in the development of tailored preventive intervention efforts for vulnerable minority youth residing in high-poverty neighborhoods.