XX and XY cells have a different number of X and Y genes. These differences in their genomes cause sex differences in the functions of cells, both in the gonads and in non‐gonadal tissues. This review discusses mouse models that have shed light on these direct genetic effects of sex chromosomes that cause sex differences in physiology. Because many sex differences in tissues are caused by different effects of male and female gonadal hormones, it is important to attempt to discriminate between direct genetic and hormonal effects. Numerous mouse models exist in which the number of X or Y genes is manipulated, aiming to observe the effects on phenotype. In two models, namely the four core genotypes model and SF1 knockout gonadless mice, it is possible to detect sex chromosome effects that are not explained by group differences in gonadal hormones. Moreover, mouse models are available to determine whether the sex chromosome effects are caused by X or Y genes.