New treatments for hematologic malignancies have led to outcomes that are outpacing the ability of traditional measures of response to accurately capture a patient's depth of response and risk of relapse. Assessment of measurable residual disease (MRD) offers a high-sensitivity evaluation for remaining disease present in a patient. MRD is not a surrogate marker for the detection of cancer cells, but rather a direct measure of them. MRD has quickly become an important measurement of response in patients with multiple myeloma and acute lymphocytic leukemia. Retrospective and prospective studies indicate that MRD-negative patients have better outcomes, particularly progression-free and overall survival, compared with patients who are MRD-positive. Two methods have emerged as the primary strategies for assessing MRD: next-generation sequencing (NGS) and next-generation flow (NGF). Both methods measure detectable disease in the bone marrow. The clonoSEQ® Assay, which uses NGS technology, is cleared by the US Food and Drug Administration for the detection and monitoring of MRD in bone marrow samples from patients with multiple myeloma or B-cell acute lymphoblastic leukemia. This monograph discusses the supporting research and clinical use of MRD assessment among patients with multiple myeloma and acute lymphoblastic leukemia.