Multiple myeloma (MM) is a plasma cell malignancy characterized by the high capacity to induce osteolytic bone lesions. Bone destruction in MM mainly depends on the increase of osteoclast formation and activity that occurs in close contact with myeloma cells infiltration. The histomorphometric studies, performed in MM patients, have demonstrated that MM patients with high plasma cell infiltrate are also characterized by a lower number of osteoblasts and a decreased bone formation that contributes, to the development of bone lesion. In the last years the progress in acknowledge of the pathophysiology of MM-induced osteolysis leaded to identify new therapeutics targets in MM bone disease and developed new drugs in the treatment of patients with skeletal involvement.