Transcription factors play essential roles in controlling normal blood development and their alteration leads to abnormalities in cell proliferation, differentiation and survival. In many childhood acute leukemias, transcription factors are altered through chromosomal translocations that change their functional properties resulting in repressed activity or inappropriate activation. The development of therapies that specifically target these molecular abnormalities holds promise for improving the outcome in diseases that remain challenging to treat, such as childhood T-cell acute lymphoblastic leukemia and acute myeloid leukemia, with improved toxicity profiles. All trans-retinoic acid and arsenic trioxide have already demonstrated efficacy in acute promyelocytic leukemia in both adults and children. Newer agents, such as histone deacetylase inhibitors, drugs targeting the NOTCH pathway, and short interfering RNAs have shown encouraging results in pre-clinical studies and are likely to enter the clinical arena in the near future. Through an improved understanding of the pathways and mechanisms underlying the malignant transformation induced by altered transcription factors, new targeted therapies will be designed that should greatly enhance current available treatments.