Background: The largest organ in the human body, the skin, serves as a physical barrier to the outside world. It also houses millions of bacteria, viruses, and fungi that protect us against invading pathogens or result in altered physiology and disease. These microorganisms can contribute to normal skin health or predispose individuals to pathogenic disorders. Surveillance and observation of the microbiome can give insight into identifying common taxa that compose our skin and indications of new or changing pathogens. However, to do this effciently, it is important to understand what can be detected from skin samples and the differences we may see using various collection methods. Methods: We used publicly available NCBI SRA RNAseq bioprojects that queried “skin,” processing 132 bioprojects with 8,274 samples. Using FastQC, Salmon, KRAKEN2, and MiCXR/Immunarch, we aimed to analyze the quality, human gene transcripts, infections, and B/T- cell responses, respectively. We aimed to identify what skin sampling method provides the best data on the skin microbiome, human gene mapping, and B/T-cell immune repertoire. This project is based on observational methods, not a specific hypothesis. Results: From the KRAKEN2 data, there were 14,383 viruses and 14,691 bacteria assessed through all “skin” BioProjects. From the extensive data pool, we identified unique BioProject signatures for protest (Leishmania), bacteria (Mycoplasma), and viruses (HSV1 dose dependencies, HPV in human warts, Chinese transmitted tick viruses, Human T-cell lymphotropic virus, and the first-ever human case of equine infectious anemia virus). The use of read mapping and coverage is critical to confirming the presence of foreign species, noted through the observation of T4 DNA ligase RNA presence prior to 2018 RNA sequencing. Once pathogens were detected, cellular response mapping was developed, yielding insights into the pathophysiology of multiple viral infections of the skin and sex differences. Conclusion: Detecting a wide variety of microorganisms on the skin can give insight into dermatological pathologies and skin physiology. Using the publicly available skin datasets, we see many unique stories of microorganisms in the skin. This big data mapping strategy highlights the importance of broad observational mapping, possible with cutting-edge sequencing tools. This work was supported by the MI-SAPPHIRE program of MDHHS and the CDC. 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.