Measurable residual disease (MRD) quantification is an essential component of caring for patients with acute lymphoblastic leukemia (ALL). Many studies in pediatric and adult populations have validated the prognostic significance of MRD early in and throughout the course of treatment for ALL, and it is generally accepted that achievement of MRD less than 10[-4] (0.01%) is a critical milestone. ALL is uniquely amenable to quantification of MRD by multiple techniques, including multiparameter flow cytometry, various allele-specific and mutation-specific quantitative polymerase chain reaction methods, and more recently amplicon-based next-generation sequencing. Quantification of MRD with these high-sensitivity methods not only facilitates risk stratification, but also is used to determine appropriateness of intensified therapy, such as allogeneic hematopoietic cell transplant, as well as MRD-targeted therapy with blinatumomab. We review the data supporting the use of MRD quantification in ALL to guide clinical decision-making.