Acute Myeloid Leukemia (AML) is an aggressive cancer type of blood that is often fatal despite improving treatments. The root cause of fatality is the resistant tumor cells relapsing shortly after the end of therapy. Therefore, there is an urgent need for investigating the molecular mechanisms governing these resistant cells. New strategies, based on this gained knowledge, should be developed to stratify patients towards the most effective therapy for preventing relapse as well as precision targeting of resistance causing tumor cells to improve the clinical outcome for AML patients. In the Joint Funding project RiskY-AML, we have thoroughly analysed the therapy resistant cells by developing new isolation parameters, investigating their non-genetic mechanisms of adapting to different therapy conditions and relapsing afterwards. This has revealed vulnerabilities, which can be exploited in development of novel drugs. Furthermore, we have developed a biomarker predicting therapy response and enabling patient stratification and novel treatment approaches, which will be validated in clinical trials.