Animal experiments have provided evidence for the presence of sex differences from the synaptic level up to behaviour. Although sex differences in the human brain may have been presumed implicitly since the days of Aristotle, research on the presence of functional and structural sex differences of the human brain started only relatively recently. The most conspicuous sex difference in the mammalian brain was described by Gorski et al.  in the preoptic area (POA) of the rat hypothalamus. We found that the volume of a putative homologue of this sexually dimorphic nucleus (SDN) in the adult human hypothalamus was more than twice as large in men as in women and contained about twice as many cells. Recently a similar sex difference and volume has been described for the human bed nucleus of the stria terminalis and ‘interstitial nuclei of the hypothalamus’ (IN AH). Sexual differentiation of the hypothalamus was generally believed to take place between 4 and 7 months of gestation. A life span study on the SDN of more than 100 subjects revealed, however, that only after the age of 2-4 years postnatally sexual differentiation becomes manifest by a decrease in volume and cell number in the female SDN. If sexual differentiation of the brain indeed takes place postnatally, not only chemical and hormonal factors may influence this process but also social factors. A prominent theory on the development of sexual orientation is that it develops as a result of an interaction between the developing brain and sex hormones. According to Dörner’s hypothesis, male homosexuals have a female differentiation of the hypothalamus. This hypothesis was not supported by our observations on the SDN. Neither the SDN volume nor the cell number in the hypothalamus of homosexual men differed from that of heterosexual men. However, a difference in SCN cell number was observed in relation to sexual orientation. The volume and cell number of the SCN of homosexual men was twice as large as that of a reference group. During development, the SCN volume and cell counts reach peak values around 13-16 months after birth. At this age the SCN contains about the same number of cells as the SCN of adult male homosexuals, whereas in the reference group the cell numbers subsequently decline to the adult value, which is about 35% of the peak value. The observation that an SCN similarly enlarged as that observed in homosexual men was present in a woman with Prader-Willi syndrome, a congenital LHRH deficiency in which sex hormones are very low, suggests that at some stage of brain development the interaction with sex hormones might be essential for the programmed SCN cell death. In conclusion, marked sex differences in the human hypothalamus are found in the SDN and BST, and an enlarged SCN is present in homosexual men. The functional implications of such differences in relation to gender and sexual orientation are, however, far from clear at the moment.