Objective: The present study investigated the long-term impact of exposure to poverty-related stressors during childhood on allostatic load, an index of physiological dysregulation, and the potential mediating role of substance use. Method: Participants (n = 162) were rural children from New York State, followed for 8 years (between the ages 9 and 17). Poverty- related stress was computed using the cumulative risk approach, assessing stressors across 9 domains, including environmental, psychosocial, and demographic factors. Allostatic load captured a range of physiological responses, including cardiovascular, hypothalamic pituitary adrenal axis, sympathetic adrenal medullary system, and metabolic activity. Smoking and alcohol/drug use were tested as mediators of the hypothesized childhood risk-adolescent allostatic load relationship. Results: Cumulative risk exposure at age 9 predicted increases in allostatic load 8 years later. Smoking, but not alcohol and drug use, was a significant mediator of the prospective, longitudinal relationship between childhood cumulative risk and adolescent allostatic load. Conclusions: The present paper contributes to the understanding of the role of early life stress in health across the life span and of the mechanisms by which adverse childhood environments impact health as children emerge into early adulthood. This knowledge will have implications for early intervention efforts. (PsycINFO Database Record (c) 2013 APA, all rights reserved).