Five kinds of cells in the BM microenvironment are depicted, as well as a few of the complex interactions among these cells and MM cells. Some of the critical survival and growth factors, such as IL-6, are made by more than one kind of BM cell. External stimuli, such as hypoxia and internal signals resulting from dysregulated MYC, stimulate HIF-1α and VEGF secretion, which in turn stimulate endothelial cells to secrete IGF-1. The hallmark uncoupling of bone remodeling is partially explained by an increase in osteoclast activity (mediated by RANKL/RANK interactions, decreased osteoprotegerin (OPG), and increased MIP-1α) and a decrease in osteoblast activity (mediated by DKK1 and IL-3). The resultant increase in osteoclast activity stimulates the survival and growth of MM cells, at least partially by increased IL-6. Potential therapeutic agents that directly inhibit some of these interactions include bisphosphonates (which inhibit osteoclast function), anti-RANKL antibody, anti-DKK1 antibody, and exogenous OPG.