Most sex differences in brain function are attributed to sex differences in the effects of gonadal secretions. In addition, however, male and female cells differ because of differential effects of sex chromosome genes expressed within the cells themselves. The latter conclusion comes from numerous studies in which sexual phenotype appears to be insensitive to the effects of sex hormones during development or cases in which sex differences develop before the onset of sex-specific patterns of gonadal secretions. Recently, mouse models have become available in which the genetic sex of brain cells is independent of the gonadal type (testes vs. ovaries), which allows a test of the role of sex chromosome genes in brain development. This paper reviews the evidence that genetic sex of brain cells influences their sexual phenotype, and critically discusses the relative advantages of various experimental approaches to study this effect.