The theoretical constructs of allostasis and allostatic load (AL) have contributed to our understanding of how constantly changing social and environmental factors impact physiological functioning and shape health and aging disparities, particularly along socioeconomic, gendered, racial, and ethnic lines. AL represents the cumulative dysregulation of biological systems with prolonged or poorly regulated allostatic responses. Nearly two decades of empirical research has focused on operationalizing the AL construct for examining the antecedents and health outcomes accompanying multisystem biological dysregulation. The purpose of this systematic review is to examine the empirical literature that quantifies the AL construct; the review also evaluates the social, environmental, and genetic antecedents of AL as well as its predictive utility for a variety of health outcomes. A total of 58 articles published between 1997 and 2012 were retrieved, analyzed, and synthesized. The results revealed considerable heterogeneity in the operationalization of AL and the measurement of AL biomarkers, making interpretations and comparisons across studies challenging. There is, however, empirical substantiation for the relationships between AL and socioeconomic status, social relationships, workplace, lifestyle, race/ethnicity, gender, stress exposure, and genetic factors. The literature also demonstrated associations between AL and physical and mental health and all-cause mortality. Targeting the antecedents of AL during key developmental periods is essential for improving public health. Priorities for future research include conducting prospective longitudinal studies, examining a broad range of antecedent allostatic challenges, and collecting reliable measures of multisystem dysregulation explicitly designed to assess AL, at multiple time points, in population-representative samples.