Osteoclastic bone resorption is a critical component of skeletal complications of malignancy including fracture, bone pain, hypercalcemia, and spinal cord compression. Three proteins, RANKL, RANK, and OPG have been recently identified as key determinants of osteoclastogenesis and the regulation of bone resorption. Both RANKL and OPG can be aberrantly regulated in the cancer setting and function as important gatekeepers of tumor-induced osteolytic bone disease. RANKL-induced osteoclastogenesis not only mediates osteolytic bone disease, but also contributes to the pathogenesis of osteoblastic bone disease resulting from tumors. In addition, an important role was recently described for bone marrow derived RANKL to mediate the bone-specific tropism of RANK-expressing tumor cells. This manuscript will review how RANKL contributes to skeletal complications of cancer and the development of targeted, mechanism-based drugs that inhibit RANKL.