Chronic myelogenous leukemia (CML) is a clonal disorder initiated by expression of the BCR/ABL fusion protein in hematopoietic stem cells (HSC), which lead to chronic over-production of myeloid cells and eventual progression to frank acute leukemia. BCR/ABL is a hyperactive and deregulated tyrosine kinase that promotes leukemic growth through perturbation of a broad range of signaling pathways involved in cell survival, proliferation, and differentiation. While a wealth of information is currently available regarding the clinical features and the molecular deregulations leading to the transformation of HSCs into leukemia-initiating stem cells (LSC) in CML, we still need to understand the differentiation pathways by which transformed HSCs generate pathological levels of myeloid cells and the contribution of the inflammatory tumor microenvironment. I will present recent works from my laboratory in mouse models of human CML, which investigate how BCR/ABL expression disrupts HSC differentiation programs and corrupts the bone marrow (BM) niche to promote disease development.