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More than 25% of Europeans suffer from a complex disease, and together these diseases account for 70% of all deaths. The use of genomic, molecular, or imaging data to develop accurate diagnostic tools for treatment recommendations and preventive strategies, and for disease prognosis and prediction, is an important step toward precision medicine. However, for complex diseases, precision medicine is associated with several challenges. There is a significant heterogeneity between patients of a specific disease\u2014both with regards to symptoms and underlying causal mechanisms\u2014and the number of underlying genetic and nongenetic risk factors is often high. Here, we summarize precision medicine approaches for complex diseases and highlight the current breakthroughs as well as the challenges. We conclude that genomic\u2010based precision medicine has been used mainly for patients with highly penetrant monogenic disease forms, such as cardiomyopathies. However, for most complex diseases\u2014including psychiatric disorders and allergies\u2014available polygenic risk scores are more probabilistic than deterministic and have not yet been validated for clinical utility. However, subclassifying patients of a specific disease into discrete homogenous subtypes based on molecular or phenotypic data is a promising strategy for improving diagnosis, prediction, treatment, prevention, and prognosis. The availability of high\u2010throughput molecular technologies, together with large collections of health data and novel data\u2010driven approaches, offers promise toward improved individual health through precision medicine.<\/jats:p>","DOI":"10.1111\/joim.13640","type":"journal-article","created":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T11:58:12Z","timestamp":1682337492000},"page":"378-396","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["Precision medicine in complex diseases\u2014Molecular subgrouping for improved prediction and treatment stratification"],"prefix":"10.1111","volume":"294","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2915-4498","authenticated-orcid":false,"given":"\u00c5sa","family":"Johansson","sequence":"first","affiliation":[{"name":"Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole A.","family":"Andreassen","sequence":"additional","affiliation":[{"name":"NORMENT Centre Division of Mental Health and Addiction Oslo University Hospital &amp; Institute of Clinical Medicine University of Oslo  Oslo Norway"},{"name":"KG Jebsen Centre for Neurodevelopment Research University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0316-5866","authenticated-orcid":false,"given":"S\u00f8ren","family":"Brunak","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Protein Research Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"},{"name":"Rigshospitalet Blegdamsvej 9 Copenhagen University Hospital  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0520-7604","authenticated-orcid":false,"given":"Paul W.","family":"Franks","sequence":"additional","affiliation":[{"name":"Genetic and Molecular Epidemiology Unit Lund University Diabetes Centre Department of Clinical Science Lund University  Lund Sweden"},{"name":"Novo Nordisk Foundation  Hellerup Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Hedman","sequence":"additional","affiliation":[{"name":"Department of Medical Biosciences Ume\u00e5 University  Ume\u00e5 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8532-5087","authenticated-orcid":false,"given":"Ruth J. 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