AbstractBruton tyrosine kinase (Btk) has long been known to play a key role in chronic lymphatic leukaemia, Waldenström macroglobulinaemia and other B‐cell proliferative disorders. An impressive programme of drug discovery and clinical development led to the approval of covalent and non‐covalent 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‐review, 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‐like 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.