Astronauts are at risk of losing 1.0 to 1.5% of their bone mass for every month they spend in space despite their adherence to high impact exercise training programs and dietary regimens designed to preserve their musculoskeletal system. This loss is the result of microgravity-related impairment of osteocyte and osteoblast function and the consequent upregulation of osteoclast-mediated bone resorption. This review describes the ontogeny of osteoclast hematopoietic stem cells, the contributions of macrophage colony stimulating factor, activator of NFkB and the calcineurin pathways make in osteoclast differentiation, and provides details of bone formation, the osteoclast cytoskeleton, the immune regulation of osteoclasts, and osteoclast mechanotransduction on Earth, in the microgravity of space, and in conditions of simulated microgravity. The article discusses the need to better understand how osteoclasts are able to function in zero gravity and reviews current and prospective therapies that may be used to treat osteoclast-mediated bone disease.