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One of the key events occurring during fetal brain development is the induction of permanent morpho-functional sexual differences in many brain areas. This “imprinting” mechanism, operating on a plastic brain within a narrow sensitive window, leads to gender-specific responses to the same stimulus both in neurochemistry/neuroendocrinology, and in some behavioral responses. The origin of CNS dimorphism is a topic that has fascinated neuroscientists for more than 60 years. The conventional view of brain sexual differentiation proposes that the masculine or feminine brain organization depends on the presence or absence of early gonadal steroid exposure: prenatal testosterone (T) surge in males induces both the masculinization and the defeminization of some brain nuclei, while in the absence of fetal gonadal hormones, as in females, the brain appears to feminize spontaneously. Some effects of T depend on its conversion to estradiol or DHT, two active metabolites formed by the enzymes aromatase and 5alpha-reductase type 2, respectively. Many studies carried out on rodents in our and in other laboratories clarified that estradiol and DHT are implicated in both masculinization and defeminization; on the contrary, T as such and DHT seem to be the main brain organizers in men. However, the most recent research, briefly discussed in this paper, has now clarified that the hormonal environment alone is not sufficient to trigger the whole process and that a precise coordination and interaction among hormonal signals, neuronal genome and the epigenome are pivotal to the genesis of brain gender-specific differentiation. Given the complexity of the whole process, it is not surprising that any external perturbation that brain sex differentiation may have heavy consequences on several parameters. Some possible variations related to prenatal exposure to environmental pollutants that interfere with the hormonal activity and/or the epigenome will be briefly analyzed in the final part of the paper.