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The endogenous oxytocin system plays a vital role in facilitating parturition, lactation and social interaction in humans and other mammals. It also impacts on a number of important endocrine, immune and neurotransmitter systems. A well-regulated oxytocin system has been proposed to increase resilience, and therefore reduce the likelihood of an individual developing mental illness or substance dependence. This review discusses the adverse external influences that can modulate oxytocin receptor and protein levels and impact on substance use and mental health. The paper highlights the impact of adversity such as poor maternal care, parental substance use and child abuse or neglect. We review clinical and preclinical data on the impact of adversity on the basis of the time of exposure from infancy and early childhood, to adolescence, adulthood to older age. Previous research suggests that dysregulation of the endogenous oxytocin system may be implicated in determining susceptibility to stress, anxiety, addiction and mental health conditions. The impact of external influence seems to be strongest in specific time periods where the system shows experience-based development or natural fluctuations in oxytocin levels. Interventions that target the oxytocin system during or soon after exposure to adversity may prove protective.