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An impressive programme of drug discovery and clinical development led to the approval of covalent and non\u2010covalent Btk inhibitors that became pillars of treatment of such malignancies. However, both a risk of cardiovascular events and the emergence of an elusive mutational landscape seem to complicate the clinical use of each Btk inhibitor. In this plain language mini\u2010review, we show that the search for better Btk inhibitors is challenged by the ancestral origin of Btk, its homology with innocent kinases in cardiovascular system and unique phylogenetic\u2010like modalities with which Btk can mutate upon exposure to one inhibitor or another. Whereas basic and clinical pharmacology is already at work to explore new avenues of Btk inhibition, phylogeny remains behind the curtain to steer achievements and failures in this field.<\/jats:p>","DOI":"10.1111\/bph.17466","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T20:48:41Z","timestamp":1738702121000},"page":"1446-1451","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Advances in Bruton tyrosine kinase (Btk) inhibition are steered by Bruton tyrosine kinase phylogeny"],"prefix":"10.1111","volume":"182","author":[{"given":"Giorgio","family":"Minotti","sequence":"first","affiliation":[{"name":"Department of Medicine and Unit of Drug Sciences Campus Bio\u2010Medico University  Rome Italy"},{"name":"Fondazione Policlinico Universitario Campus Bio\u2010Medico and Unit of Clinical Pharmacology  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Camilli","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Fondazione Policlinico Universitario A. 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