Jane E. Churpek, MD, from the University of Chicago, Chicago, IL, describes the importance of assessing the germline composition in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) at the International Symposium on Acute Leukemias (ISAL) 2017 in Munich, Germany. She explains that the germline is typically used as a comparison to identify acquired mutations, however, she argues that we should focus on the germline to determine the proportion of patients with a germline predisposition to leukemia. Dr Churpek highlights that when a new gene implicated in developing leukemia is found, this can lead to an understanding of the mechanism of leukemogenesis. An example of this is DDX41, which is found to be mutated in a significant proportion of adult onset familial leukemia, and understanding how DDX41 operates, and how it interacts with aging to cause late onset familial MDS, can help in the development of rational and targeted therapies. Dr Churpek describes another example, where it was found that individuals with mutations in ANKRD26, RUNX1 and ETV6 had similar phenotypes. This led to the discovery that RUNX1 binds to an area in the untranslated region of the ANKRD26 gene where mutational clusters were found, resulting in an upregulation of ANKRD26 and increased MAPK signaling. Blocking MAPK signaling can rescue the platelet phenotype in these patients, providing a rationale for mechanism based therapies.