Objective: Acute stress provides many beneficial effects whereas chronic stress contributes to a variety of human health issues including anxiety, depression, gastrointestinal problems, cardiac disease, sleep disorders and obesity. The goal of this work was to identify, using a rodent model, hippocampal gene signatures associated with prolonged chronic stress representing candidate biomarkers and therapeutic targets for early diagnosis and pharmacological intervention for stress induced disease. Materials & methods: Mice underwent ‘restraint stress’ over 7 consecutive days and hippocampal gene-expression changes were analyzed at 3, 12 and 24 h following the final restraint treatment. Results: Data indicated that mice exposed to chronic restraint stress exhibit a differential gene-expression profile compared with non-stressed controls. The greatest differences were observed 12 and 24 h following the final stress test. Conclusion: Our study indicated that Gpr88, Ttr, Gh and Tac1 mRNAs were modulated in mice exposed to chronic restraint stress. These transcripts represent a panel of biomarkers and druggable targets for further analysis in the context of chronic stress associated disease in humans. Original submitted 17 September 2014; Revision submitted 12 January 2015