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Understanding the molecular mechanisms underlying adaptations to these demands is crucial for developing strategies to enhance human performance and resilience in such environments. This review integrates multi-omics data across a range of extreme phenotypes, including astronauts, scuba divers, acute alcohol consumers, long-haul flight passengers, bodybuilders, and simulation racers. We analyze current literature in genomic, transcriptomic, proteomic, metabolomic, and metagenomic studies to identify common and phenotype-specific adaptations, highlighting potential biomarkers and pathways associated with resilience in harsh conditions. This integrated approach offers insights into human adaptability and provides a foundation for developing personalized strategies to mitigate risks and enhance performance in extreme environments, with particular relevance to extended spaceflight.<\/jats:p>","DOI":"10.3390\/life15091377","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T08:28:15Z","timestamp":1756715295000},"page":"1377","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Multi-Omics Profiling of Individuals Sustaining Extreme Physical Stressors"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4873-1932","authenticated-orcid":false,"given":"Anurag","family":"Sakharkar","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, 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