This review provides an overview of the biology and pathogenic mechanisms of tumor necrosis factor (TNF), a pleiotropic cytokine with significant roles in both homeostasis and disease pathogenesis. Recent advancements have elucidated new concepts that offer potential therapeutic strategies for TNF-mediated diseases. The model of TNF receptor (TNFR) signaling has been expanded to include linear ubiquitination and the formation of distinct signaling complexes, which are linked to various functional outcomes such as inflammation, apoptosis, and necroptosis. The discovery of epigenetic mechanisms and cellular priming, tolerization, and short-term transcriptional memory has enriched our understanding of TNF-induced gene expression. Identification of distinct homeostatic or pathogenic TNF-induced signaling pathways has led to the concept of selectively inhibiting the detrimental effects of TNF while preserving its homeostatic functions. The review discusses the latest discoveries in TNF-induced signal transduction, including the roles of TNFR1 and TNFR2, and the fine-tuning of TNFR signaling through negative regulators. It also explores the cell-type specificity and epigenetic regulation of TNF-induced gene expression, as well as the expression kinetics of TNF-inducible genes. The review highlights the altered cellular responses to other stimuli, such as priming and tolerization, and the role of TNF in health and disease, including its homeostatic functions and pathogenic functions in inflammatory and autoimmune diseases. Finally, it discusses emerging therapeutic strategies, including the limitations of global TNF inhibition, improving TNF blockade, reducing immunogenicity, controlling TNF synthesis, and inhibiting intracellular responses.This review provides an overview of the biology and pathogenic mechanisms of tumor necrosis factor (TNF), a pleiotropic cytokine with significant roles in both homeostasis and disease pathogenesis. Recent advancements have elucidated new concepts that offer potential therapeutic strategies for TNF-mediated diseases. The model of TNF receptor (TNFR) signaling has been expanded to include linear ubiquitination and the formation of distinct signaling complexes, which are linked to various functional outcomes such as inflammation, apoptosis, and necroptosis. The discovery of epigenetic mechanisms and cellular priming, tolerization, and short-term transcriptional memory has enriched our understanding of TNF-induced gene expression. Identification of distinct homeostatic or pathogenic TNF-induced signaling pathways has led to the concept of selectively inhibiting the detrimental effects of TNF while preserving its homeostatic functions. The review discusses the latest discoveries in TNF-induced signal transduction, including the roles of TNFR1 and TNFR2, and the fine-tuning of TNFR signaling through negative regulators. It also explores the cell-type specificity and epigenetic regulation of TNF-induced gene expression, as well as the expression kinetics of TNF-inducible genes. The review highlights the altered cellular responses to other stimuli, such as priming and tolerization, and the role of TNF in health and disease, including its homeostatic functions and pathogenic functions in inflammatory and autoimmune diseases. Finally, it discusses emerging therapeutic strategies, including the limitations of global TNF inhibition, improving TNF blockade, reducing immunogenicity, controlling TNF synthesis, and inhibiting intracellular responses.