T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that requires treatment with intensified chemotherapy. Studies of the long-term effects of chemotherapy in patients with T-ALL showed that recent gains in leukemia-free survival have been achieved at the cost of significant increases in the rates of life-threatening and debilitating toxicities. Thus, further advances in the treatment of T-ALL require the development of effective and highly specific molecularly targeted antileukemic drugs. The identification of cMYB translocations and duplications in human T-ALL suggests an important oncogenic role for this transcription factor during T-cell transformation. Nevertheless, the exact molecular mechanisms by which cMYB contributes to the pathology of this disease remains unclear. Here, we aim to identify the role of enhanced MYB activity in enhancer driven oncogenic transcription in the context of malignant T-cell development and investigate the in vivo role of cMyb in the initiation and maintenance of T-ALL. Importantly, these novel insights in the pathogenic role of cMYB in T-cell leukemia will provide new avenues for therapeutic intervention in this aggressive human malignancy.