Osteoclasts are multinucleated cells of hematopoietic origin that are responsible forthe degradation of old bone matrix. Osteoclast differentiation and activity are controlledby two essential cytokines, macrophage colony-stimulating factor (M-CSF) andthe receptor activator of nuclear factor-?B ligand (RANKL). M-CSF and RANKL bindto their respective receptors c-Fms and RANK to stimulate osteoclast differentiationthrough regulation of delicate signaling systems. Here, we summarize the critical oressential signaling pathways for osteoclast differentiation including M-CSF-c-Fms signaling,RANKL-RANK signaling, and costimulatory signaling for RANK.