Receptor activator of nuclear factor-κB ligand (RANKL) is a key factor in osteoclastogenesis and bone resorption and has been established as a therapeutic target in skeletal pathologies, including osteoporosis and bone metastases. However, RANKL expression has been demonstrated in extraskeletal tissues, and thus a potential role for RANKL beyond its function in bone biology has been emphasized by the discovery of a multitude of pleiotropic nonskeletal effects. In this chapter, we will summarize the role of RANKL in mammary gland development and tumorigenesis, cancer cell migration and metastasis, the development and function of the immune system, and thermoregulation.