Paget's disease is characterized by markedly increased osteoclast formation and bone resorption followed by excessive new bone formation. Osteoclasts in Paget's disease are increased both in number and size, contain paramyxoviral‐like nuclear inclusions, and can have up to 100 nuclei per cell. Marrow culture studies have identified several abnormalities in osteoclast formation in Paget's disease. Osteoclast‐like multinucleated cells formed more rapidly in marrow cultures from patients with Paget's disease, produced increased levels of inter‐leukin‐6 (IL‐6), and expressed high levels of IL‐6 receptors compared to normals. IL‐6 levels were also increased in bone marrow and peripheral blood of patients with Paget's disease. In addition, osteoclast precursors from patients with Paget's disease are hyperresponsive to 1,25‐dihydroxyvitamin D₃ (1,25(OH)₂D₃) and calcitonin. The increased sensitivity of osteoclast precursors to 1,25(OH)₂D₃ is mediated through the vitamin D receptor (VDR), since 24‐hydroxylase activity is also up‐regulated at concentrations of 1,25(OH)₂D₃ that are one log less than that needed to induce 24‐hydroxylase activity in osteoclast precursors from normals. However, VDR numbers and affinity for 1,25(OH)₂D₃ do not differ in osteoclast precursors from Paget's patients compared to those from normals. Synergistic interactions between cytokines such as IL‐6 and 1,25(OH)₂D₃ also cannot explain the enhanced sensitivity of osteoclast precursors from patients with Paget's disease to 1,25(OH)₂D₃. Interestingly, coculture studies of osteoclast precursors and cells from the marrow microenvironment of patients with Paget's disease and normals have demonstrated that the marrow microenvironment is more osteoclastogenic than normal. Thus, studies of the cell biology of osteoclasts in Paget's disease have demonstrated an increased rate of osteoclast formation and abnormalities in both osteoclast precursors and the marrow microenvironment Enhanced IL‐6 production by osteoclasts in Paget's disease may further amplify the increased osteoclast formation already ongoing in the pagetic lesion, and may explain the increased bone turnover at uninvolved sites distant from the pagetic lesion.