T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that accounts for 15% of pediatric and 25% of adult ALL cases. Despite extensive characterization of the (epi)genetic mechanisms driving T-ALL, patients are currently still treated with intensive chemotherapeutic regimens. Even with aggressive treatments, relapse occurs in about 15% of pediatric and 40% of adult T-ALL patients and is associated with dismal outcome. The main prognostic factor in T-ALL is minimal residual disease (MRD) measured at the end of induction, which reflects the amount of persisting residual tumor cells. Based on MRD, chemotherapy treatment is adjusted to attain remission and in some patients hematopoietic stem cell transplantation will be indicated. Importantly however, MRD cells are not direct therapeutic targets. Our current preliminary in vivo data in T-ALL xenograft models point out that several targetable pathways are upregulated in response to short-term chemotherapy and thus might represent biological vulnerabilities at MRD. With this study, we aim to define patient-specific T-ALL MRD signatures to identify targeted treatment options. We propose a model for a therapeutic strategy where residual tumor cells are targeted early after chemotherapy initiation to tackle emergence of therapy resistance early on. This approach could increase therapy efficacy and further decrease the risk for relapse development.