BACKGROUND: Adaptation to stress is critical for survival. The adrenal medulla, the major source of epinephrine, plays an important role in the development of the hyperadenergic state and increased risk for stress associated disorders, such as hypertension and myocardial infarction. The transcription factor Egr1 plays a central role in acute and repeated stress, however the complexity of the response suggests that other transcription factor pathways might be playing equally important roles during acute and repeated stress. Therefore, we sought to discover such factors by applying a systems approach.RESULTS: Using microarrays and network analysis we show here for the first time that the transcription factor signal transducer and activator of transcription 3 (Stat3) gene is activated in acute stress whereas the prolactin releasing hormone (Prlh11) and chromogranin B (Chgb) genes are induced in repeated immobilization stress and that along with Egr1 may be critical mediators of the stress response.CONCLUSIONS: Our results suggest possible involvement of Stat3 and Prlh1/Chgb up-regulation in the transition from short to repeated stress activation.