A comprehensive analysis of gene expression differences between sexes in multiple somatic tissues of 334 mice derived from an intercross between inbred strains C57BL/6J and C3H/HeJ revealed extensive sexually dimorphic gene expression. Thousands of genes showed sexual dimorphism in liver, adipose, and muscle, while hundreds were sexually dimorphic in brain. These genes exhibited tissue-specific expression patterns and were enriched for distinct pathways. They also showed chromosomal enrichment, not only on sex chromosomes but also on several autosomes. Genetic analyses indicated global regulation of subsets of these genes, with many controlled by expression quantitative trait loci (eQTL) hotspots. Tissue-specific transcription factor binding sites were also enriched in these genes. Sexual dimorphism in gene expression was observed in liver, adipose, whole brain, and muscle. The number of significantly differentially expressed genes varied between tissues, with the highest in liver and the lowest in brain. These genes were involved in diverse biological functions, including immune response, lipid metabolism, and cell signaling. The study identified many novel sexually dimorphic genes, particularly in brain, which could help explain sex differences in neurological and psychiatric diseases. The sexually dimorphic genes were highly tissue-specific, with minimal overlap between tissues. Functional categories varied significantly between tissues, with liver genes enriched for protease inhibitor activity, immune response, and lipid metabolism, while brain genes were enriched for RNA helicase activity. Chromosomal analysis revealed enrichment of sexually dimorphic genes on sex chromosomes, particularly the X chromosome, and on several autosomes in a tissue-specific manner. Transcription factor binding site (TFBS) analysis showed tissue-specific enrichment of TFBS, with brain genes showing significant enrichment for four transcription factors. eQTL analysis identified regulatory hotspots for sexually dimorphic genes in liver and adipose, with some genes showing cis-eQTL. These findings suggest that sexually dimorphic genes are regulated by tissue-specific genetic mechanisms. The study provides evidence for tissue-specific genetic and transcriptional regulation of sexually dimorphic genes, highlighting the importance of understanding these mechanisms in the context of sex differences in disease susceptibility and drug response. The results underscore the need for further research into the molecular basis of sexual dimorphism in gene expression and its implications for health and disease.A comprehensive analysis of gene expression differences between sexes in multiple somatic tissues of 334 mice derived from an intercross between inbred strains C57BL/6J and C3H/HeJ revealed extensive sexually dimorphic gene expression. Thousands of genes showed sexual dimorphism in liver, adipose, and muscle, while hundreds were sexually dimorphic in brain. These genes exhibited tissue-specific expression patterns and were enriched for distinct pathways. They also showed chromosomal enrichment, not only on sex chromosomes but also on several autosomes. Genetic analyses indicated global regulation of subsets of these genes, with many controlled by expression quantitative trait loci (eQTL) hotspots. Tissue-specific transcription factor binding sites were also enriched in these genes. Sexual dimorphism in gene expression was observed in liver, adipose, whole brain, and muscle. The number of significantly differentially expressed genes varied between tissues, with the highest in liver and the lowest in brain. These genes were involved in diverse biological functions, including immune response, lipid metabolism, and cell signaling. The study identified many novel sexually dimorphic genes, particularly in brain, which could help explain sex differences in neurological and psychiatric diseases. The sexually dimorphic genes were highly tissue-specific, with minimal overlap between tissues. Functional categories varied significantly between tissues, with liver genes enriched for protease inhibitor activity, immune response, and lipid metabolism, while brain genes were enriched for RNA helicase activity. Chromosomal analysis revealed enrichment of sexually dimorphic genes on sex chromosomes, particularly the X chromosome, and on several autosomes in a tissue-specific manner. Transcription factor binding site (TFBS) analysis showed tissue-specific enrichment of TFBS, with brain genes showing significant enrichment for four transcription factors. eQTL analysis identified regulatory hotspots for sexually dimorphic genes in liver and adipose, with some genes showing cis-eQTL. These findings suggest that sexually dimorphic genes are regulated by tissue-specific genetic mechanisms. The study provides evidence for tissue-specific genetic and transcriptional regulation of sexually dimorphic genes, highlighting the importance of understanding these mechanisms in the context of sex differences in disease susceptibility and drug response. The results underscore the need for further research into the molecular basis of sexual dimorphism in gene expression and its implications for health and disease.