Fragile X syndrome is a common inherited form of mental retardation and originates from the absence of expression of the FMR1 gene. This gene and its two homologues, FXR1 and FXR2, encode for a family of fragile X related (FXR) proteins with similar tissue distribution, together with sequence and functional homology. Based on these characteristics, it has been suggested that these proteins might partly complement one another. To unravel the function of Fxr2 protein, the expression pattern of 12,588 genes was studied in the brains of wild-type and Fxr2 knockout mice, an animal model which shows behavioral abnormalities partly similar to those observed in Fmr1-knockout mice. By genome expression profiling and stringent significance tests we identify genes and gene groups de-regulated in the brains of Fxr2 knockout mice. Differential expression of candidate genes was validated by real-time PCR, in situ hybridization, immunohistochemistry and western blot analysis. A number of differentially expressed genes associated with the Fxr2 phenotype have been previously involved in other memory or cognitive disorders.