NF-κB is a key transcription factor regulating innate and adaptive immune responses and inflammatory processes. It induces pro-inflammatory genes, including cytokines and chemokines, and participates in inflammasome regulation. NF-κB also controls the survival, activation, and differentiation of immune cells, and its dysregulation contributes to inflammatory diseases. The NF-κB pathway has two main activation routes: canonical and noncanonical. The canonical pathway involves IKK-mediated degradation of IκBα, while the noncanonical pathway relies on p100 processing via NIK. NF-κB is crucial in innate immune cells, such as macrophages, where it mediates inflammation through cytokine production and T-cell activation. In T cells, NF-κB regulates differentiation into Th1, Th17, and Tfh cells, and is involved in Treg development. NF-κB also plays a role in inflammasome activation, contributing to inflammatory diseases. Inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and atherosclerosis are associated with NF-κB dysregulation. Therapeutic strategies targeting NF-κB include inhibitors of IKK, proteasome inhibitors, and drugs that block NF-κB nuclear translocation or DNA binding. Despite progress in developing NF-κB inhibitors, challenges remain in achieving effective and safe therapies. Understanding the specific mechanisms of NF-κB activation in different diseases is essential for developing targeted treatments.NF-κB is a key transcription factor regulating innate and adaptive immune responses and inflammatory processes. It induces pro-inflammatory genes, including cytokines and chemokines, and participates in inflammasome regulation. NF-κB also controls the survival, activation, and differentiation of immune cells, and its dysregulation contributes to inflammatory diseases. The NF-κB pathway has two main activation routes: canonical and noncanonical. The canonical pathway involves IKK-mediated degradation of IκBα, while the noncanonical pathway relies on p100 processing via NIK. NF-κB is crucial in innate immune cells, such as macrophages, where it mediates inflammation through cytokine production and T-cell activation. In T cells, NF-κB regulates differentiation into Th1, Th17, and Tfh cells, and is involved in Treg development. NF-κB also plays a role in inflammasome activation, contributing to inflammatory diseases. Inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and atherosclerosis are associated with NF-κB dysregulation. Therapeutic strategies targeting NF-κB include inhibitors of IKK, proteasome inhibitors, and drugs that block NF-κB nuclear translocation or DNA binding. Despite progress in developing NF-κB inhibitors, challenges remain in achieving effective and safe therapies. Understanding the specific mechanisms of NF-κB activation in different diseases is essential for developing targeted treatments.