B-lineage and myeloid leukemia cells are often transformed by the same oncogenes, but have different biological and clinical characteristics. Although B-lineage acute lymphoblastic leukemia (B-ALL) cells are characterized by a state of chronic energy deficit, myeloid leukemia cells show abundant energy reserve. Interestingly, fasting has been demonstrated to inhibit selectively the development of B-ALL but not myeloid leukemia, further suggesting that lineage identity may be linked to divergent metabolic states in hematopoietic malignancies. The B-lymphoid transcription factors IKZF1, EBF1, and PAX5 are essential for early B-cell development and commitment to B-cell identity. However, in >80% of human pre-B-ALL cases, the leukemic clones harbor genetic lesions of these transcription factors. The significance of these defects has only recently been investigated. Here, we discuss the unexpected function of a B-lymphoid transcriptional program as a metabolic barrier against malignant transformation of B-cell precursor cells. The metabolic gatekeeper function of B-lymphoid transcription factors may force silent preleukemic clones carrying potentially oncogenic lesions to remain in a latent state. In addition, this program sets the threshold for responses to glucocorticoids in pre-B-ALL. Finally, the link between the tumor-suppressor and metabolic functions of B-lymphoid transcription factors is matched by observations in clinical trials: obesity and hyperglycemia are associated with poor clinical outcome in patients with pre-B-ALL.