Acamprosate (calcium acetylhomotaurinate) has been used for the treatment of alcoholism for over 20 years, and while early evidence suggested it modulates the function of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype, its precise mechanism of action has yet to be determined. In order to further understand how acamprosate acts within the central nervous system, we conducted a whole genome microarray study of the mouse frontal cortex following repeated administration of saline or acamprosate (200 mg/kg i.p.) twice daily for 5 days. Differental gene expression analysis revealed that the expression of a total of 113 genes was changed as a result of acamprosate treatment (53 up-regulated, 60 down-regulated, p<0.01 for each gene). Changes were observed in genes encoding proteins involved in regulation of transcription, post-translational modification, cellular metabolism, neurotransmission, cell-cell communication, lipid signaling, protein phosphorylation, immune cell function, structural function, and appetite regulation. These findings indicate that acamprosate induces changes in the expression of numerous genes in the frontal cortex, and further investigation is needed into which of these gene or genes contribute to its mechanism of action.