Rheumatoid arthritis(RA)is the most common inflammatory disease of the musculoskeletal system primarily affecting the joints.It is characterized by massive synovial hyperplasia and subsequent destruction of articular cartilage and bone.Although various aspects in the pathogenesis of RA remain unclear,genetic,environmental and of course immunological factors have been involved.Defects in apoptosis seem to play a role in both initiation and perpetuation of RA.Apo2 ligand/tumor necrosis factor(TNF)related apoptosis-inducing ligand(Apo2L/TRAIL)is a cytokine that belongs to the TNF superfamily capable of inducing apoptosis on tumor cells through activation of the extrinsic pathway.Besides this function,like other members of the TNF superfamily,Apo2L/TRAIL has been shown to exert important functions in the regulation of the immune system.Concerning pathological conditions,the Apo2L/TRAIL signaling pathway plays an important role in the response to infections,in immune surveillance against tumors and in autoimmune diseases such as RA.Furthermore,its implication in suppression of autoimmu-nity suggests that Apo2L/TRAIL has potential as therapeutic agent not only in cancer but also in autoimmune diseases.In fact,Apo2L/TRAIL-based therapies have been shown effective in various animal models of RA.This review summarizes the current knowledge on the biology of Apo2L/TRAIL and its role in RA. Rheumatoid arthritis (RA) is the most common inflammatory disease of the musculoskeletal system in affecting the joints. It is characterized by massive synovial hyperplasia and subsequent destruction of articular cartilage and bone. Although various aspects in the pathogenesis of RA remain unclear, genetic, environmental and of course immunological factors have been involved. Defects in apoptosis seem to play a role in both initiation and perpetuation of RA. Apo2 ligand / tumor necrosis factor (TNF) related apoptosis-inducing ligand (Apo2L / TRAIL) is a cytokine that belongs to the TNF superfamily capable of inducing apoptosis on tumor cells through activation of the extrinsic pathway. Beside this function, like other members of the TNF superfamily, Apo2L / TRAIL has been shown to exert important functions in the regulation of the immune system. Configuration pathological conditions , the Apo2L / TRAIL signaling pathway plays an important role in the response to infections, in immune surveillance against tu mors and in autoimmune diseases such as RA. Futurerther, its implication in suppression of autoimmu-nity suggests that Apo2L / TRAIL has potential as therapeutic agent not only in cancer but also in autoimmune diseases. In fact, Apo2L / TRAIL-based therapies have been shown effective in various animal models of RA. This review summarizes the current knowledge on the biology of Apo2L / TRAIL and its role in RA.