An early transient increase in brain polyamine (PA) metabolism, termed the PA-stress-response (PSR), is a common reaction to stressful stimuli, including physical, emotional, and hormonal stressors, with a magnitude related to the stress intensity. In the extreme, traumatic injury can result in an incomplete PSR, with persistent accumulation of putrescine and eventual reduction in the concentrations of the higher polyamines (PAs), spermidine and spermine. Chronic intermittent application of stressors causes a recurrence of the brain PSR, but, in contrast, it leads to habituation of the response in the periphery (liver). Severe continuous stress, however, may lead to accumulation of brain PAs. Long-term inhibition of PA synthesis depletes brain PAs and can result in altered emotional reactivity to stressors. Furthermore, the brain PSR, in contrast to the periphery, can be blocked by a long-term, but not by short-term, treatment with lithium, the most efficacious treatment of manic–depressive illness. The brain PSR is developmentally regulated, and the switch to the mature pattern coincides with the cessation of the “stress hyporesponsive period” in the hypothalamic–pituitary–adrenocortical (HPA) system. In contrast to the brain and liver, the PSR in the adrenal and thymus is down-regulated by acute stressors. Transient up-regulation of the PSR, as in the brain and liver, is implicated in cell survival while its down-regulation is implicated in cell death. Taken together, the findings indicate that the PSR is a dynamic process that varies with the type, intensity, and duration of stressors, and implicate this response as an adaptive mechanism in the reaction to stressful events. Under persistent stressful conditions, however, the PSR may be maladaptive as may be reflected by PA accumulation. This raises the hypothesis that proper regulation of brain PSR may be critical for neuronal function and for an appropriate behavioral response to stressors.