TNF-alpha is a pleiotropic cytokine involved in the regulation of various biological effects, including cell survival and proliferation, cell differentiation, and cell death. Moreover, TNF-alpha triggers proinflammatory responses, essentially through its ability to promote the expression of various proinflammatory genes. Most of the biological effects initiated by TNF-alpha rely on its ability to bind to and activate TNF-R1. As a consequence, molecular complexes are being formed, resulting from the recruitment of multiple adaptor proteins to the intracellular TNF-R1 DD. The adaptor protein FAN constitutively binds to a proximal membrane domain of TNF-R1 called NSD. Herein, the role of FAN in TNF-alpha-induced cell signaling and biological responses is discussed.