Abstract: Benzene can induce acute myeloid leukemia and probably other hematological malignancies. At very low exposure level (below OELs in China 6 mg/m³), it is still reported that benzene causes hematotoxicity. Therefore, the health risk assessment of benzene exposure, at low levels is needed. This article presents the probable mechanism by which benzene induces leukemia, involving the interference to the targeting of critical genes and pathways, the induction of genetic, chromosomal or epigenetic abnormalities and genomic instability. These effects can be modulated by benzene-induced oxidative stress and reduce immune-surveillance and finally lead to the generation of leukemic stem cells and subsequent clonal evolution to leukemia. The mechanism of benzene-induced hematotoxicity is very complicated, an integrated approach for benzene risk assessment is recommended. The application of toxicogenomics and systems biology in human populations, animals and in vitro models of the HSC stem cell niche are suggested. These approaches will help us understand the mechanisms of benzene toxicity and identify the potential biomarkers of exposure, early effect and susceptibility, which will be useful for risk assessment.