In addition to their primary function of platelet production, a growing body of evidence suggests that megakaryocytes play a critical role in regulating bone mass and hematopoiesis through their interaction with osteoblasts, as well as hematopoietic derived cells including: osteoclasts, osteal macrophages or osteomacs, and hematopoietietic stem cells. Several mouse models exist whereby high numbers of megakaryocytes result in up to a 300% increase in bone volume. Megakaryocytes increase osteoblast proliferation (>6-fold increase), while simultaneously inhibiting osteoclast development (>10-fold reduction), leading to a net increase in bone formation. In addition to increasing osteoblast proliferation in vitro, megakaryocytes stimulate a dramatic 3-6 fold increase in osteomac proliferation in vitro. Further, megakaryocytes also regulate, primarily through their impact on osteoblasts and osteomacs, hematopoietic stem cell proliferation and function in vitro and in vivo. Importantly, recent studies have shown that aging critically impacts these interactions. For example, while old megakaryocytes also increase osteoblast proliferation in vitro, the fold-increase is markedly reduced. Of note, while in vivo transplantation of young GATA1low/low hematopoietic cells (containing high numbers of young megakaryocytes) resulted in a robust increase in bone mass, transplantation of old GATA1low/low hematopoietic cells did not result in a significant change in bone mass. This may in part be a function of the altered role aged megakaryocytes play in regulating osteoclasts. Indeed, rather than inhibiting osteoclast development as seen with young megakaryocyte conditioned medium, aged megakaryocyte conditioned medium promotes osteoclastogenesis. While more work is needed to dissect the exact mechanisms by which aging alters megakaryocyte-mediated functions, it appears that identifying ways to preserve youthful megakaryocytes or to alter aged megakaryocyte function may be important for reducing bone loss associated with age-related osteoporosis as well as improving aging hematopoietic stem cell function.