This review provides an overview of the biology and signaling mechanisms of tumor necrosis factor (TNF), a pleiotropic cytokine with significant biological and clinical importance. TNF was first identified as a cytokine capable of exerting antitumoral effects in mouse models, and its structure and function have been extensively studied since then. TNF is primarily produced as a type II transmembrane protein and can be released as a soluble form via proteolytic cleavage. The TNF receptor (TNF-R) family, consisting of TNF-R1 and TNF-R2, binds both membrane-integrated and soluble TNF, mediating various cellular responses. TNF-R1 is constitutively expressed in most tissues and plays a key role in the immune response, while TNF-R2 is highly regulated and found primarily in immune cells. The review highlights the complex mechanisms of TNF signaling, including the activation of nuclear factor kappa B (NF-κB), JNK, and p38-MAPK pathways. It also discusses the role of TRADD, TRAF2, RIP, and other signaling molecules in these pathways. Additionally, the review explores the multifaceted roles of TNF in inflammation, tissue regeneration, and disease, emphasizing the importance of context-specific responses. Finally, it touches on the potential therapeutic applications of TNF-based treatments, such as in autoimmune diseases and cancer.This review provides an overview of the biology and signaling mechanisms of tumor necrosis factor (TNF), a pleiotropic cytokine with significant biological and clinical importance. TNF was first identified as a cytokine capable of exerting antitumoral effects in mouse models, and its structure and function have been extensively studied since then. TNF is primarily produced as a type II transmembrane protein and can be released as a soluble form via proteolytic cleavage. The TNF receptor (TNF-R) family, consisting of TNF-R1 and TNF-R2, binds both membrane-integrated and soluble TNF, mediating various cellular responses. TNF-R1 is constitutively expressed in most tissues and plays a key role in the immune response, while TNF-R2 is highly regulated and found primarily in immune cells. The review highlights the complex mechanisms of TNF signaling, including the activation of nuclear factor kappa B (NF-κB), JNK, and p38-MAPK pathways. It also discusses the role of TRADD, TRAF2, RIP, and other signaling molecules in these pathways. Additionally, the review explores the multifaceted roles of TNF in inflammation, tissue regeneration, and disease, emphasizing the importance of context-specific responses. Finally, it touches on the potential therapeutic applications of TNF-based treatments, such as in autoimmune diseases and cancer.