Bone and immune systems are tightly linked. In the past years, many molecules originally believed to belong to the immune system were found to function in bone cells. It is now evident that the two systems are coregulated by many shared cytokines and signaling molecules. Here we exemplify the complex interaction between bone metabolism and immune response focusing on the multifaceted role of receptor activator of NF-κB ligand (RANKL). RANKL is expressed by cells of both systems, is an essential regulator of bone degradation and exerts either pro or anti-inflammatory effects on the immune response. In the present review, we summarize the multiple functions of RANKL in bone and in the immune systems, aiming to provide an overview of the field of osteoimmunology.