Both cellular as well as extracellular matrix components of the stem cell microenvironment, or niche, are critical in stem cell regulation. Recent data highlight a central role for osteoblasts and their by-product osteopontin as a key part of the hematopoietic stem cell (HSC) niche. Herein we describe a model for the yin and yang of HSC regulation mediated by osteoblasts. In this respect, osteoblasts synthesise proteins with opposing effects on HSC proliferation and differentiation highlighting their pivotal role in adult hematopoiesis. Although osteoblasts play a central role in HSC regulation other stromal and microenvironmental cell types and their extracellular matrix proteins also contribute to this biology. For example, the glycosaminoglycan hyaluronic acid as well as the membrane bound form of stem cell factor are also key regulators of HSC. Osteopontin and these "niche" molecules are not only involved in regulation of HSC quiescence but also effect HSC homing, trans-marrow migration and lodgement. Accordingly this leads us to expand upon Schofield's niche hypothesis: we propose that the HSC niche is critical for attraction of primitive hematopoietic progenitors to the endosteal region and tightly tethering them within this location, and by doing so placing them into intimate contact with cells such as osteoblasts whose cellular products are able to exquisitely regulate their fate.