This paper reviews the Window of Tolerance model of the long-term effects of the severe emotional trauma associated with childhood abuse, a model which can also be applied to adult trauma of sufficient severity to cause post-traumatic stress disorder, chronic dysthymic disorders and chronic anxiety disorders. Dysfunctional behaviours such as deliberate self-harm and substance abuse are seen as efforts to regulate an autonomic nervous system which is readily triggered into extreme states by reminders of the original traumatic events. While midbrain areas such as the periaqueductal gray mediate instant defence responses to traumatic events and their memory triggers it is proposed that ascending monoaminergic tracts are implicated in longer-term changes in mood and arousal. An imbalance of ascending dopaminergic tracts may drive rapid fluctuations in level of arousal and in the associated mood, drive and motivation. Animal models of depression frequently use traumatic experiences of pain, isolation or social defeat to induce changes in mesolimbic and mesocortical dopamine systems which may alter prefrontal cortical control of midbrain defence responses. A focus on the pharmacology of the Window of Tolerance could provide advances in drug treatments for promoting emotional regulation in those who are suffering from the chronic sequelae of traumatic experiences.