Sex differences in psychosis and their interaction with laterality (systematic departures from 50:50 left-right symmetry across the antero-posterior neural axis) are reviewed in the context of the X-Y gene hypothesis. Aspects of laterality (handedness/cerebral asymmetry/the torque) predict (1) verbal and non-verbal ability in childhood and across adult life and (2) anatomical, physiological, and linguistic variation relating to psychosis. Neuropsychological and MRI evidence from individuals with sex chromosome aneuploidies indicates that laterality is associated with an X-Y homologous gene pair. Within each mammalian species the complement of such X-Y gene pairs reflects their potential to account for taxon-specific sexual dimorphisms. As a consequence of the mechanism of meiotic suppression of unpaired chromosomes <MSUC> such X-Y gene pairs generate epigenetic variation around a species defining motif that is carried to the zygote with potential to initiate embryonic gene expression in XX or XY format. The Protocadherin11XY (PCDH11XY) gene pair in Xq21.3/Yp11.2 in probable coordination with a gene or genes within PAR2 (the second pseudo-autosomal region) is the prime candidate in relation to cerebral asymmetry and psychosis in Homo sapiens. The lately-described pattern of sequence variation associated with psychosis on the autosomes may reflect a component of the human genome's adjustment to selective pressures generated by the sexually dimorphic mate recognition system. © 2013 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by John Wiley and Sons, Ltd.