<p>Sex chromosomes are a fundamental aspect of sex-biased biology, but the extent to which homologous X–Y gene pairs (‘the gametologs’) contribute to sex-biased phenotypes remains hotly debated. Although these genes tend to exhibit large sex differences in expression throughout the body (XX females can express both X members, and XY males can express one X and one Y member), there is conflicting evidence regarding the degree of functional divergence between the X and Y members. Here we develop and apply co-expression fingerprint analysis to characterize functional divergence between the X and Y members of 17 gametolog gene pairs across &gt;40 human tissues. Gametolog pairs exhibit functional divergence between the sexes that is driven by divergence between the X versus Y members (assayed in males), and this within-pair divergence is greatest among pairs with evolutionarily distant X and Y members. These patterns reflect that X versus Y gametologs show coordinated patterns of asymmetric coupling with large sets of autosomal genes, which are enriched for functional pathways and gene sets implicated in sex-biased biology and disease. Our findings suggest that the X versus Y gametologs have diverged in function and prioritize specific gametolog pairs for future targeted experimental studies.</p>