Zeb2 is a member of the ZEB family of transcriptional regulators. Its expression has been correlated with the formation and/or function of cancer stem cells and metastatic spread in solid tumors. We have previously demonstrated that Zeb2 is highly expressed in the hematopoietic system and evidence from mouse retroviral mutagenesis screens point to a role for Zeb2 in leukemia. Here, we examined the roles of Zeb2 in the hematopoietic system and in leukemia formation through a conditional gain-of-function approach. Zeb2 expression from the ROSA26 locus resulted in altered T cell development and partial block in differentiation observed at the DN3 pre-T cell stage. In addition, Zeb2 overexpressing mice spontaneously develop T-ALL starting at 5 months of age, indicating that Zeb2 can act as a driver in T cell malignancies. Breeding these mice onto a tumor-prone background (using conditional p53 knock-outs) we have observed a significant decrease in tumor latency and an increase of the stem/progenitor markers c-Kit and CD44, suggesting an increase in leukemic stem cells. Using a minimal dilution series of tumor cells into NOD/SCID mice we could demonstrate a 10-100-fold increase in leukemia-initiating cells in the Zeb2 overexpressing tumors. To assess the relevance of these findings with human disease, we screened a cohort of T-ALL patients and found increased expression of ZEB2 predominantly associated with the immature/ETP-ALL patient group. Early T-cell precursor leukemia (ETP-ALL) is a high-risk subtype of human leukemia that is poorly understood at the molecular level. Here, we report translocations targeting Zeb2 as well as decreased miR200 family expression in ETP-ALL that can result in increased Zeb2 expression. Zeb2driven mouse leukemia recapitulates important features of human ETP-ALL, including enhanced leukemia-initiation potential and activated JAK/STAT signaling through transcriptional activation of IL7R. This study therefore reveals ZEB2 as a novel oncogene in immature T-ALL.