The use of DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane) in some countries, although regulated, is contributing to an increased worldwide risk of exposure to this organochlorine pesticide or its derivative p,p'-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene]. Many studies have associated p,p'-DDE exposure to type 2 diabetes, obesity and alterations of the reproductive system, but their molecular mechanisms of toxicity remain poorly understood. We have addressed this issue by using commercial microarrays based on probes for the entire Mus musculus genome to determine the hepatic transcriptional signatures of p,p'-DDE in the phylogenetically close mouse species Mus spretus. High-stringency hybridization conditions and analysis assured reliable results, which were also verified, in part, by qRT-PCR, immunoblotting and/or enzymatic activity. Our data linked 198 deregulated genes to mitochondrial dysfunction and perturbations of central signaling pathways (kinases, lipids, and retinoic acid) leading to enhanced lipogenesis and aerobic glycolysis, inflammation, cell proliferation and testosterone catabolism and excretion. Alterations of transcript levels of genes encoding enzymes involved in testosterone catabolism and excretion would explain the relationships established between p,p´-DDE exposure and reproductive disorders, obesity and diabetes. Further studies will help to fully understand the molecular basis of p,p´-DDE molecular toxicity in liver and reproductive organs, to identify effective exposure biomarkers and perhaps to design efficient p,p'-DDE exposure counteractive strategies.