The skeletal tissue is closely associated with the hematopoietic tissue lodged in its inner cavities. Besides the well-known role of the endosteal osteoblasts in the maintenance of the hematopoietic stem cell (HSC) niche, it is an emerging concept that osteoclasts are involved in the regulation of hematopoiesis as well, although published data are still incomplete and somehow controversial. We reviewed the literature, and report here our perspective on the close relationship between bone resorption and HSC permanence in bone or egress to the circulation. We discussed the pressure that bone diseases exert on the development of hematological alterations, as well as the role of calcium and osteoclast enzymes in the regulation of HSC homeostasis. Genetic studies and preclinical experiments are described, which unveiled how bone disorders and treatments aimed at restoring the bone mass affect hematopoiesis, with consequent clinical implications. We conclude that this new field of investigation must be extended to unequivocally establish the role of osteoclasts in myelopoiesis and lymphopoiesis, and to envision treatments that can help hematological failures to be cured along with the associated bone alterations.