Turnover balance of extracellular matrix (ECM) is a prerequisite for the structural and functional homeostasis of bone marrow (BM) microenvironment. The role of ECM in physiologic hematopoiesis and its pathologic change in hematopoietic malignancies are very important and under extensive investigation. Accumulating evidence suggests that matrix metalloproteinases (MMPs), a family of zinc-dependent proteinases, take an active part in the physiological and pathological hematopoiesis through remodeling the ECM in BM hematopoietic microenvironment. In this review, we will focus on the roles of MMPs in physiological hematopoiesis, hematopoietic stem cells mobilization/transplantation, and hematological malignancies. Furthermore, the preclinical studies on the role of synthetic MMP inhibitors in the treatment of hematological malignancies will be discussed.