In most psychiatric disorders, stress is the major nongenomic factor that contributes to the expression or exacerbation of acute symptoms, recurrence or relapse after a period of remission, and treatment outcome. Delineation of mechanisms by which stress contributes to these processes is fundamental to understanding the disease process and for improving outcome. In this article, evidence is reviewed to indicate that many central aspects of stress response, including activation of the hypothalmic-pituitary-adrenal (HPA) axis and dopamine neurotransmission, are modulated, and in some cases mediated, by glutamate neurotransmission in the prefrontal cortex (PFC). It is suggested that activation of glutamatergic neurotransmission in the PFC presents a common mechanism by which stress influences normal and abnormal processes that sustain affect and cognition. Although monoamines, in particular dopamine, have been considered the major culprits in the adverse effects of stress in disorders such as addiction and schizophrenia, it is likely that in a vulnerable brain with an underlying PFC pathophysiology, abnormal stress-activated monoaminergic neurotransmission is secondary to anomalies in cortical glutamate neurotransmission. Thus, understanding the contribution of glutamate-mediated processes to stress response through the use of experimental models that involve disrupted PFC function can provide insights to the fundamental pathophysiology of stress-sensitive psychiatric disorders and lead to novel strategies for treatment and prevention.