While several catecholaminergic systems are activated by stressful stimuli, the mesoprefrontal dopamine (DA) system appears to be particularly vulnerable to stress. Low intensity stressors that do not produce detectable effects in most ascending catecholaminergic systems activate mesoprefrontal DA neurons. Mesoprefrontal DA neurons are unique in that they lack or have decreased densities of specific autoreceptors affecting autoregulatory capabilities, which could contribute to the fact that mesoprefrontal DA neurons exhibit increased rates of burst firing and DA turnover relative to other midbrain dopaminergic projections. In addition, mesoprefrontal DA neurons are uniquely modulated by a number of chemically distinct afferent influences including gamma-aminobutyric acid (GABA), serotonin, excitatory amino acid, substance P, opiate, and noradrenergic systems. Any or all of these factors could contribute to the selective activation of mesoprefrontal DA neurons following exposure to low intensity stressors. The present review summarizes the possible mechanisms by which mesoprefrontal DA neurons are preferentially activated by stress. The operational significance of this unique neurochemical response to stress is discussed in terms of a possible coping versus anxiety function. Also discussed are the ramifications of a dysfunction of this system with respect to stress-related or exacerbated disorders such as post-traumatic stress disorder and schizophrenia.