The bone marrow microenvironment (BMM) plays a critical role in hematopoietic stem cells (HSCs) maintenance and regulation. There is increasing interest in the role of the BMM in promoting leukemia stem cell (LSC) maintenance, resistance to conventional chemotherapy and targeted therapies, and ultimately disease relapse. Recent studies have enhanced our understanding of how the BMM regulates quiescence, self-renewal, and differentiation of LSC. In this comprehensive review, we discuss recent advances in our understanding of the crosstalk between the BMM and LSC, and the critical signaling pathways underlying these interactions. We also discuss potential approaches to exploit these observations to create novel strategies for targeting therapy-resistant LSC to achieve relapse-free survival in leukemic patients. © 2015 Elsevier Inc.