Metastatic cancer cells that secrete elevated levels of DKK1 disrupt the balance of osteoblastogenesis and osteoclastogenesis in favor of an osteolytic microenvironment that is conducive to tumor growth. MM has a unique and absolute requirement for the bone marrow microenvironment for its growth and survival and MM plasma cells may cultivate this “soil” by synthesizing and secreting DKK1. The primary effect of DKK1 appears to be the disruption of the differention of MSC in the osteoblasts (OB). RANK signaling regulates osteoclast development and Wnt signaling in MSC/OB differentially regulates RANKL and OPG, a RANKL decoy, which together modulate osteoclast development. DKK1 suppression of Wnt in MSC/OB leads to increased production of RANKL and IL-6 and decreased production of OPG. The shift in RANKL:OPG ratios leads to increased osteoclastogenesis and IL-6 is a potent survival factor of MM cells. The subsequent loss of osteoblasts and increase in osteoclasts causes lytic bone destruction, hypercalcemia, and loss of normal bone marrow function. A vicious cycle of bone destruction and tumor growth ensues. The absence of DKK1 in a subset of MM suggests that other soluble factors produced by MM cells may contribute to this process. These include MIP1a, sFRP-2, IL-3, RANKL, and possibly sFRP-3 (see “Proposed model of DKK1-mediated promotion of bone metastases” for more details).