Osteolytic bone disease is the most debilitating manifestation of myeloma. However, myeloma-induced effects on the bone-active cells in the bone marrow are more than just a manifestation of disease--the myeloma derives essential support from the changed balance between bone-forming and -resorbing cells. This observation has lead to the notion that effective control of myeloma bone disease by reducing osteoclast activity and restoring osteoblast activity will contribute to long-term control of myeloma progression. Unlike osteolysis associated with other tumors that metastasize to bone, myeloma-associated lytic lesions are unique in that they do not repair even after many years in complete remission, reflecting a total loss of osteoblastic activity in areas of myeloma foci, apparently induced by the myeloma. Advances in imaging technology including positron emission tomography-computed tomography scanning allows accurate detection of lytic lesions and the monitoring of treatment effects. Effective antimyeloma therapy combined with anti-osteoclast drugs can halt the progression of osteolysis; in severe cases with vertebral compression fractures, effective physical support in the form of vertebroplasty or kyphoplasty is required for control of function, pain, and stature. Fractures of the long bones are usually treated by intramedullary rod placement. New approaches to enhance osteoblast activity while controlling osteoclast activity currently under investigation may prove effective in controlling lytic bone disease and myeloma progression.