The brains of males and females, men and women, are different-that is a fact. What is debated is how different and how important those differences are. Sex differences in the brain are determined by genetics, hormones, and experience, which in humans includes culture, society, and parental and peer expectations. The importance of nonbiological variables to sex differences in humans is paramount, making it difficult if not impossible to parse out those contributions that are truly biological. The study of animals provides us the opportunity to understand the magnitude and scope of biologically based sex differences in the brain and understanding the cellular mechanisms provides us insight into novel sources of brain plasticity. Many sex differences are established during a developmental sensitive window by differences in the hormonal milieu of males versus females. The neonatal testis produces large amounts of testosterone, which gains access to the brain and is further metabolized into active androgens and estrogens, which modify brain development. Major parameters that are influenced by hormones include neurogenesis, cell death, neurochemical phenotype, axonal and dendritic growth, and synaptogenesis. Variance in these parameters results in sex differences in the size of particular brain regions, the projections between brain regions, and the number and type of synapses within particular brain regions. The cellular mechanisms are both region and endpoint specific and invoke many surprising systems such as prostaglandins, endocannabinoids, and cell death proteins. By understanding when, why, and how sex differences in the brain are established, we may also learn the source of strong gender biases in the relative risk and severity of numerous neurological diseases and disorders of mental health, including but not limited to autism, dyslexia, attention deficit disorder, schizophrenia, Alzheimer's, multiple sclerosis, Parkinson's, and major depressive disorder.