In this issue, McMahon and colleagues demonstrate that secondary clinical resistance to the FLT3 inhibitor gilteritinib in relapsed acute myeloid leukemia is often polyclonal and commonly mediated by heterogeneous mutations that activate downstream RAS–MAPK pathways. These fi ndings and recent data from others indicate that emergence of multiple clones, each with distinct mechanisms of resistance, is a common finding at secondary failure of single-agent–targeted therapies for relapsed leukemias.