The brain is a sexually dimorphic organ. Little is known about molecular mechanisms underlying sexual differentiation of the brain and behavior. The classical hypothesis of brain sexual differentiation suggests that a perinatal surge of organizational sex hormones secreted from the gonad leads to irreversible changes in morphology of the brain, followed by pubertal hormones that activate neural networks to express sex-specific behavioral phenotypes. However, recent studies propose that sex hormones are not the sole factor to establish sexual dimorphism in the brain. Since mammalian sex strictly relies on sex chromosome complement, i.e., XY for males and XX for females, intrinsic genetic differences between XY and XX cells are strong candidates for the cause of sexual dimorphism. Several genes on the Y chromosome are expressed in the male brain and may act in a dominant manner. Among these Y-linked genes, the testis-determining gene Sry is of particular interest. Although SRY is known to function as a transcriptional activator triggering testicular genetic pathway, several lines of evidence suggest that it also acts as an epigenetic regulator. This chapter provides a basic overview of mammalian sex determination and brain sexual differentiation. It summarizes current evidence of brain-specific epigenetic gene regulations in mammals and other species, and explores the common features between them. Potential roles of Sry during brain sexual development are described and prospects of this research field are discussed.