Background: As social definitions of sex and gender expand, there is a greater demand for understanding the clinical challenges of intersex individuals, transgender individuals, and those with hormonal and transcriptomic profiles that do not align with traditional binary standards. Larger population studies are elucidating comorbidities associated with Klinefelter’s Syndrome, Turner’s Syndrome, 47XXX, 47XYY, and other sex chromosome syndromes even though the sex chromosomes are underpowered in traditional GWAS. Though research has focused on how estrogen and testosterone supplementation can influence comorbidity risk, we identify a need for greater understanding of isoform and tissue-specific expression and functions of X and Y genes to understand their potential interactions with hormones and inform physiological outcomes. Methods: Analysis of RNA-Sequencing data quantified in transcripts per million (TPM) from GTex (extracted June 2022, n = 17,382), NCBI SRA Blood PAXgene tube analysis (extracted June 2021, n = 12,559), and NCBI SRA “skin” RNA sequencing (extracted June 2021, n = 8,274). Results: We display an expression panel of 572 isoforms of 73 sex-biased genes across 54 male (n = 11,588) and female (n=5,798) tissue samples and highlight isoform-specific expression differences within the brain, arteries, heart, skeletal muscle, and gastrointestinal tract. Six X/Y gene pairs show broad ratios over tissues highlighting the role of X-chromosome dosage and X-chromosome inactivation escape differences in various tissues. Several genome-wide eQTLs across multiple tissues have sex differences and are found within X/Y chromosome transcription factor binding sites such as ZFX/ZFY. Stratifying blood and skin RNA-Sequencing data by XIST/KDM5D ratios to determine transcriptomic “sex”, we conduct an exploratory analysis of bioprojects with five or more outliers of X:Y chromosome expression ratios (Males: PRJNA683803 (HIV), PRJNA768419 (Sepsis), PRJNA492829 (Vaccine trial), PRJNA496323 (Psoriasis and atopic dermatitis), PRJNA699562 (COVID-19). Females: PRJNA683803 (HIV), PRJNA794277 (Sepsis), PRJNA492965 (Vaccine trial), PRJNA526259 (Myalgic encephalomyelitis)).Conclusion: Transcriptomics enables broader insights to sex chromosomes and their contributions to physiology outside of the binary male/female knowledge. This work was supported by the NIH NIAID and OD grant R01AI171984. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.