RANKL plays a pivotal role in the differentiation, function and survival of osteoclasts, the principal bone-resorbing cells. RANKL exerts the effects by binding RANK, the receptor activator of NF-κB, in osteoclasts and its precursors. Upon binding RANKL, RANK activates six major signaling pathways: NFATc1, NF-κB, Akt/ PKB, JNK, ERK and p38, which play distinct roles in osteoclast differentiation, function and survival. Recent studies have not only provided more insights into RANK signaling but have also revealed that several factors, including INF-γ, IFN-β, and ITAM-activated costimulatory signals, regulate osteoclastogenesis via direct cross-talk with RANK signaling. It was recently shown that RANK contains three functional motifs capable of mediating osteoclastogenesis. Moreover, although both IFN-γ and IFN-β inhibit osteoclastogenesis, they exert the inhibitory effects by distinct mechanisms. Whereas IFN-γ has been shown to block osteoclastogenesis by promoting degradation of TRAF6, IFN-β inhibits osteoclastogenesis by down-regulating c-fos expression. In contrast, the ITAM-activated costimulatory signals positively regulate osteoclastogenesis by mediating the activation of NFATc1 through two ITAM-harboring adaptors: FcRγ and DAP12. This review is focused on discussing the current understanding of RANK signaling and signaling crosstalk between RANK and the various factors in osteoclasts. © 2005 IUBMB.