Normal hematopoiesis is maintained by dynamic interactions between hematopoietic cells and the bone marrow microenvironment. In hematological malignancies, there are reciprocal interactions between leukemic cells and cells of the bone marrow microenvironment such as stroma, osteoblasts and endothelium. In this review, we will discuss the influence of the microenvironment on the evolution of the leukemic phenotype. We propose that specific niches within the bone marrow microenvironment may provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death and allow acquisition of a drug-resistant phenotype. We will also discuss recent studies that suggest novel therapeutic interventions targeting the microenvironment/leukemia interaction. Focus on this stroma-leukemia crosstalk may result in the development of strategies that alleviate the acquisition of a chemoresistant phenotype and enhance the efficacy of therapies in hematological malignancies.