Emerging data show that megakaryocytes MKs) play a role in the replication and development of bone cells. Both in vivo and in vitro evidence now show that MKs can have significant effects on cells of the osteoclast OC) and osteoblast OB) lineage with obvious manifestations on bone phenotype and probable significance for human pathology. There are currently four mouse models in which increases in MK number lead to a specific bone pathology of markedly increased bone volume. While these models all achieve megakaryocytosis by different mechanisms the resultant osteosclerotic phenotype observed is consistent across all models. In vitro data suggest that MKs play a role in OC and OB proliferation and differentiation. While MKs express receptor activator of nuclear factor kappa B ligand (RANKL) a prerequisite for osteoclastogenesis they also express many factors known to inhibit OC development and co-cultures of MKs with OCs show a significant decrease in osteoclastogenesis. In contrast MKs express several proteins with a known critical role in osteoblastogenesis and bone formation and co-cultures of these two lineages result in up to a six-fold increase in OB proliferation and alterations in OB differentiation. This research demonstrates the complex regulatory interactions at play between MKs and bone cells and opens up potential targets for therapeutic intervention.