The origin and propagation of normal and leukemic hematopoietic cells critically depend on their interplays with the hematopoietic microenvironment (or so-called niche), which represent important biological models for understanding organogenesis and tumorigenesis. Nevertheless, the anatomic and functional characterizations of the niche cells for normal hematopoietic stem cells (HSCs) have proved a formidable task. It is uncertain whether the combinational effects of a few sets of molecular niche elements, behind the long-sought cellular architectures with preferred anatomic locations, actually meets the functional definition of HSC niche. Moreover, even much less is known about the niche components for numerous types of leukemia-stem cells (LSCs) that originate via discrete cellular and molecular transforming mechanisms. However, one interesting scenario is emerging, i.e., the leukemia cells can positively remodel the hematopoietic microenvironment favorable for their competition over the normal hematopoiesis that co-exists within the same eco-system. This property probably represents a previously unappreciated essential trait of a functional LSC. Obviously, the further exploration into how the hematopoietic microenvironment interplay with normal or malignant hematopoiesis will shed light onto the designing of novel types of niche-targeting therapies for leukemia.