In recent years, the identification of minimal residual disease (MRD) that persists after chemotherapy has emerged as the most powerful tool in determining the prognosis of patients with ALL, often superseding historically relevant prognostic factors. Multiple methods to detect MRD exist, each with their own advantages and disadvantages. Multiparameter flow cytometry and quantitative polymerase chain reaction are the most commonly used methods of MRD detection in clinical practice, although there is promise in the use of more sensitive assays utilizing next-generation sequencing that may be able to further refine MRD-based risk stratification. By accurately identifying patients with persistent MRD who are at highest risk for relapse, we may be able to better design rational post-remission therapies using novel agents, such as inotuzumab ozogamicin, blinatumomab, and CD19-directed chimeric antigen receptor T cells, all of which have been shown to be effective in achieving MRD negativity, even in patients with relapsed or refractory disease. Future studies will be required to determine whether these post-remission strategies can obviate the need for allogeneic stem cell transplantation for patients with ALL in whom MRD can be eradicated.