Philipp Greif, MD, from the University Hospital Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany, discusses the evolution acute myeloid leukemia (AML) relapse at the International Symposium on Acute Leukemias (ISAL) 2017 in Munich, Germany, and describes the challenge of finding the drivers of disease progression. Sequencing of AML patient samples is used to look at clonal architecture and to identify different competing clones. Dr Greif explains that by following patients over time, changes in clonal architecture can be seen, which are partly due to the selective pressure of therapy. Evolutionary patterns correlate with the clinical course of patients. When mutations are gained during the course of disease, this correlates with a later relapse, suggesting that leukemia cells need to acquire additional mutations to become therapy resistant. Two main clinical implications of this are that firstly, some of the gained mutations are responsible for chemotherapy resistance, such as in the histone demethylase gene family. Secondly, relapse drivers can sometimes be detected at a low level at diagnosis, indicating that if certain subclones are detected at diagnosis, the patient is unlikely to respond to standard therapy alone, and other options, such as allogeneic bone marrow transplantation, should be explored.