In this review, we discuss the use of measurable residual disease (MRD) in AML, ALL, and chronic myeloid leukemia (CML). Our aims were to review the different methodologies for MRD assessment; describe the clinical relevance and medical decision making on the basis of MRD; compare and contrast the usage of MRD across AML, ALL, and CML; and discuss what patients need to know about MRD as it relates to their disease status and treatment. Finally, we discuss ongoing challenges and future directions with the goal of optimizing MRD usage in leukemia management.