Myeloma bone disease is characterized by osteolytic bone destruction that is not followed by reactive new bone formation. This results in a purely lytic process, which differs from other cancers that metastasize to bone where bone destruction is followed by new bone formation. The bone destructive process in myeloma is mediated by the osteoclast (OCL), the normal bone resorbing cell. Factors that increase OCL formation and activity are produced by both myeloma cells themselves, as well as by marrow stromal cells when myeloma cells bind to marrow stromal cells. The bone destructive process releases factors that further increase the growth and survival of myeloma cells. Thus, there is a symbiotic relationship between the bone destructive process and increased growth of myeloma cells. Several studies have shown that blocking bone destruction can result in decreased tumor burden in animal models of myeloma. This overview will focus on the factors recently identified that appear to play an important role in the bone destructive process in myeloma.