The selection pressure may allow the emergence of clones presenting mutations insensitive to the targeted therapy either appearing de novo by mutation or pre-existing in small numbers and gradually replacing the sensitive cells, the latter hypothesis being favored in mathematical models, at least in CLL in the context of treatment with a Bruton tyrosine kinase (BTK) inhibitor [40]. The gene discussed is BTK; the disease is B-cell chronic lymphocytic leukemia.