TNF receptor 1 [TNF-R1; CD120a] is a 55kDa type I transmembrane protein member of the TNF receptor superfamily and it is a receptor for TNF-α and homotrimeric lymphotoxin-α. It is essential for proper development of lymph node germinal centers and Peyer’s patches and for combating intracellular pathogens. Through the building of complexes this receptor can activate the transcription factor NF-κB, mediate apoptosis and function as a regulator of inflammation. Anti-apoptotic protein BCL2-associated athanogene 4 (BAG4/SODD) and adapter proteins TRADD and TRAF2 have been shown to interact with this receptor and thus play regulatory roles in the signal transduction mediated by the receptor. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis.TNF-R1 is stored in the Golgi and translocates to the cell surface following pro-inflammatory stimuli. TNF-α stabilizes TNF-R1 and induces its sequestering in lipid rafts, where it activates NF-κB and is cleaved by ADAM-17/TACE. Release of the cleaved TNF-R1 ECD helps to resolve inflammatory reactions, since it down-regulates cell surface TNF-R1 and provides soluble TNF-R1 to bind TNF-α. Mutations in humans have been shown to be associated with the tumor necrosis factor associated periodic syndrome (TRAPS) or periodic fever syndrome and with several neurological pathologies.