: Differential display of mRNA was used to identify concordant changes in gene expression induced by two mood‐stabilizing agents, lithium and valproate (VPA). Both treatments, on chronic administration, increased mRNA levels of the transcription factor polyomavirus enhancer‐binding protein (PEBP) 2β in frontal cortex (FCx). Both treatments also increased the DNA binding activity of PEBP2αβ and robustly increased the levels of bcl‐2 (known to be transcriptionally regulated by PEBP2) in FCx. Immunohistochemical studies revealed a marked increase in the number of bcl‐2‐immunoreactive cells in layers 2 and 3 of FCx. These novel findings represent the first report of medication‐induced increases in CNS bcl‐2 levels and may have implications not only for mood disorders, but also for long‐term treatment of various neurodegenerative disorders.