Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell malignancies characterized by high clinical and molecular heterogeneity and poor outcomes. Effective treatments for these disorders remain unmet clinical needs, particularly after failure to first-line therapies. Recent studies have uncovered that the hierarchical organization of MDS and AML stem cells and their progeny, which sustain and propagate the disease, follows specific patterns that reflect the founding stem cells' differentiation capacity and transcriptional states. These cell identity traits determine signaling dependencies, thereby dictating drug sensitivity. The association between hematopoietic hierarchies and drug response has been best described for venetoclax, a proapoptotic agent that has emerged as a powerful therapeutic tool for the treatment of AML and, possibly in the near future, high-risk (HR) MDS. The finding that hematopoietic hierarchies define biologically-distinct disease subtypes has important translational and clinical implications. It will not only be critical in the near future for the selection, follow-up and post-failure management of AML and HR-MDS patients treated with venetoclax, but it should also be considered in drug discovery, therapy selection and patient stratification in clinical trials. This review provides an overview of the current understanding of healthy hematopoiesis and abnormal hematopoietic stem cell hierarchies in MDS and AML, and summarizes the growing body of evidence that these hierarchies determine sensitivity to venetoclax and other agents. Lastly, we address the translational and clinical implications of these findings and offer a critical discussion on how they may be used toward improving patient outcomes.