Simple SummaryLeukemia stem cells (LSCs) are rare cell populations present in acute myeloid leukemia (AML) that are resistant to chemotherapy and cause disease relapse in patients even after initial therapy-induced disease remission. Minimal or measurable disease detection (MRD) allows for estimating the residual disease burden after chemotherapy and helps in clinical management of the patient with AML. However, due to current technical limitations, LSCs are not routinely detected as part of MRD assessment, and there is a lack of a standard guideline for quantifying LSCs as part of MRD. This review discusses current research advancements in LSC detection during MRD and outlines future directions for making progress with such research and clinical practice. Such information will be useful to clinicians and biomedical researchers who are trying to advance the field, as well as to the broader research community seeking insight into the pathobiology of and clinical management strategies for AML.AbstractAcute myeloid leukemia (AML) is a hematological malignancy characterized by an abundance of incompletely matured or immature clonally derived hematopoietic precursors called leukemic blasts. Rare leukemia stem cells (LSCs) that can self-renew as well as give rise to leukemic progenitors comprising the bulk of leukemic blasts are considered the cellular reservoir of disease initiation and maintenance. LSCs are widely thought to be relatively resistant as well as adaptive to chemotherapy and can cause disease relapse. Therefore, it is imperative to understand the molecular bases of LSC forms and functions during different stages of disease progression, so we can more accurately identify these cells and design therapies to target them. Irrespective of the morphological, cytogenetic, and cellular heterogeneity of AML, the uniform, singularly important and independently significant prognosticator of disease response to therapy and patient outcome is measurable or minimal residual disease (MRD) detection, defined by residual disease detection below the morphology-based 5% blast threshold. The importance of LSC identification and frequency estimation during MRD detection, in order to make MRD more effective in predicting disease relapse and modifying therapeutic regimen is becoming increasingly apparent. This review focuses on summarizing functional and cellular composition-based LSC identification and linking those studies to current techniques of MRD detection to suggest LSC-inclusive MRD detection as well as outline outstanding questions that need to be addressed to improve the future of AML clinical management and treatment outcomes.