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Annually, RDs account for over $1 trillion of annual US healthcare expenditures. Despite advances in genomic medicine, it takes 5\u20138 years on average to obtain an accurate diagnosis, and less than 5% of RDs currently have FDA-approved therapies. In this article, we review the history of RD diagnosis and current healthcare gaps underlying the major failures in patient care. Next, we will highlight emerging advances in genomic medicine and AI that are rapidly changing the RD landscape. Finally, we propose a target future state that integrates agentic AI for diagnosis and therapy with human-in-the-loop feedback.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The rare disease diagnostic and therapeutic odyssey represents healthcare\u2019s most persistent failure mode. Ongoing challenges for clinical implementation involve biological modeling, manufacturing bottlenecks, and clinical trial design. We propose strategies for artificial intelligence to restructure the traditional sequence of diagnosis-then-therapy into a proactive orchestrated system delivering personalized cures at scale.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s12553-026-01057-y","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T06:36:32Z","timestamp":1773124592000},"page":"621-632","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Unifying the odyssey: artificial intelligence for rare disease diagnosis and therapy"],"prefix":"10.1007","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9455-1350","authenticated-orcid":false,"given":"Mai-Lan","family":"Ho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8530-7228","authenticated-orcid":false,"given":"Marinka","family":"Zitnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronen","family":"Azachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0599-6332","authenticated-orcid":false,"given":"Sanjay","family":"Basu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8030-3727","authenticated-orcid":false,"given":"Pranav","family":"Rajpurkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Sidlow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"1057_CR1","unstructured":"Rare Diseases. 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