The origin of relapse in acute myeloid leukaemia (AML) is thought to be due to drug-promoted mutagenesis or to the selection of drug-resistant cells. Shlush et al. provide evidence for the latter and propose at least two distinct patterns of relapse in AML. In some patients, relapse can occur from a small subpopulation of a genetically diverse pool of leukaemia stem cells already present at diagnosis. In other patients, relapse can occur from larger subpopulations of phenotypically committed leukaemia cells that have a stem cell-like transcriptional signature. This shows that targeting stem cell properties is crucial to prevent relapse.