Osteoclasts (OCs) are the cells uniquely responsible for dissolving both the organic and inorganic components of bone during bone development and remodeling throughout life. These cells originate from hematopoietic precursors of the monocyte/macrophage lineage that are present both in the bone marrow and peripheral circulation, and their numbers and/or activity are frequently increased in a wide array of clinical disorders that are associated with excessive bone loss and affect millions of people (1). For many years, investigations into how OCs develop and function have been hampered by the considerable difficulties associated with isolating and culturing these normally rare cells. Whereas cell lines have frequently provided an invaluable research tool and are widely used to decipher mechanisms involved in osteoblast (OB) differentiation and bone formation, no immortalized cell lines for mature OCs exist and the few pre-OC cell lines that have been reported either do not undergo full OC differentiation (2,3) or involve coculture systems and cells that may not be readily available to all researchers (4–6). To compound the problem further, it has proven difficult or impossible until recently to generate reliably bone-resorptive OCs expressing mature OC characteristics from primary bone marrow or circulating precursor cells in vitro. However, recent breakthroughs have now made the latter possible owing to the identification of the key signal, receptor activator of nuclear factor κB ligand (RANKL), that is responsible for the full development and activation of OCs both in vitro and in vivo (7–9).