Intriguingly, subclonality of mutation-bearing or BCL-XL/MCL1-overexpressing CLL cells has been observed even in samples obtained at the time of relapse or disease progression, implying a significant role of the permissive microenvironment and cooperating genetic and epigenetic events in driving acquired venetoclax resistance leading to overt clinical relapse [12,13,14,20,22,23]. The gene discussed is BCL2L1; the disease is B-cell chronic lymphocytic leukemia.