Multiple myeloma (MM) is a B cell malignancy characterized by uncontrolled expansion of malignant plasma cells within the bone marrow that contribute to formation of multiple osteolytic bone disease and severe skeletal devastation. Recently, direct and indirect observations suggest that fusion events between cells housed within the MM marrow microenvironment often occur and may play a role in tumor progression, including myeloma bone disease (MBD). A number of cells resident in the marrow, such as myeloid progenitors and dendritic cells, have inherited fusogenicity and osteoclastogenic potential due to the expression of a number of fusogenic proteins as well as a high sensitivity to fusogenic factors produced within the MM marrow milieu. Similarly, osteoclasts (OC), as bone-resorbing multinucleated cells resulting from the fusion of marrow monocyte/ macrophages, have been reported to improperly fuse with malignant plasma cells and drive transition of these cells into OC-like cells exerting bone-resorbing capacity. Further, based on indirect cytogenetic and molecular evidence, it has been proposed that MM cells may generate a hybrid progeny with high metastatic potential and drug resistance, ultimately pointing to uncontrolled homotypic fusions that accelerate MBD progression.