NF-κB, a key transcription factor, has been studied for 25 years, revealing significant progress in understanding its role in gene regulation and disease. NF-κB is crucial for immune system development and function, and its dysregulation contributes to inflammatory and autoimmune diseases. It also influences cell survival, differentiation, and proliferation, playing a role in various diseases including cancer, neurodegenerative disorders, and metabolic conditions. NF-κB is regulated by the IKK complex, IκB proteins, and the NF-κB dimers. The IKK complex, which includes IKKα, IKKβ, and NEMO, is essential for NF-κB activation. The IκB proteins inhibit NF-κB by phosphorylation, ubiquitination, and degradation, allowing NF-κB to translocate to the nucleus and regulate gene expression. NF-κB signaling pathways are classified into canonical and noncanonical pathways, with the canonical pathway involving IKKβ and the noncanonical pathway involving IKKα. The activation of NF-κB is triggered by various stimuli, including cytokines, pattern recognition receptors, and antigen receptors. The signaling pathways involve adapter proteins that facilitate the assembly of signaling complexes, leading to IKK activation and NF-κB transcriptional activity. Despite significant progress, many questions remain about the regulation of NF-κB, including the mechanisms of IKK activation, substrate specificity, and the role of higher-order signaling complexes. The structure of the IKK complex and its interaction with adapter proteins provide insights into the mechanisms of NF-κB activation. The study of NF-κB has led to a better understanding of its role in disease and has highlighted the importance of its regulation in maintaining physiological balance.NF-κB, a key transcription factor, has been studied for 25 years, revealing significant progress in understanding its role in gene regulation and disease. NF-κB is crucial for immune system development and function, and its dysregulation contributes to inflammatory and autoimmune diseases. It also influences cell survival, differentiation, and proliferation, playing a role in various diseases including cancer, neurodegenerative disorders, and metabolic conditions. NF-κB is regulated by the IKK complex, IκB proteins, and the NF-κB dimers. The IKK complex, which includes IKKα, IKKβ, and NEMO, is essential for NF-κB activation. The IκB proteins inhibit NF-κB by phosphorylation, ubiquitination, and degradation, allowing NF-κB to translocate to the nucleus and regulate gene expression. NF-κB signaling pathways are classified into canonical and noncanonical pathways, with the canonical pathway involving IKKβ and the noncanonical pathway involving IKKα. The activation of NF-κB is triggered by various stimuli, including cytokines, pattern recognition receptors, and antigen receptors. The signaling pathways involve adapter proteins that facilitate the assembly of signaling complexes, leading to IKK activation and NF-κB transcriptional activity. Despite significant progress, many questions remain about the regulation of NF-κB, including the mechanisms of IKK activation, substrate specificity, and the role of higher-order signaling complexes. The structure of the IKK complex and its interaction with adapter proteins provide insights into the mechanisms of NF-κB activation. The study of NF-κB has led to a better understanding of its role in disease and has highlighted the importance of its regulation in maintaining physiological balance.