The transcription factor NF-κB plays a crucial role in regulating innate and adaptive immune functions and inflammatory responses. NF-κB induces the expression of pro-inflammatory genes, participates in inflammasome regulation, and regulates the survival, activation, and differentiation of innate immune cells and inflammatory T cells. Deregulated NF-κB activation contributes to various inflammatory diseases. This review discusses the activation and function of NF-κB in inflammatory diseases and highlights therapeutic strategies based on NF-κB inhibition. The canonical and noncanonical NF-κB pathways are involved in different aspects of immune responses, with the canonical pathway being more extensively studied. NF-κB is involved in the induction of pro-inflammatory cytokines, chemokines, and inflammatory mediators in innate immune cells, as well as in the differentiation and effector function of inflammatory T cells. NF-κB also regulates inflammasome activation, which is crucial for the initiation and development of inflammatory diseases. Targeting NF-κB signaling represents an attractive approach for treating inflammatory diseases, with several categories of inhibitors being developed. However, the balance between efficacy and safety must be carefully considered, as NF-κB is also essential for maintaining normal immune responses and cell survival.The transcription factor NF-κB plays a crucial role in regulating innate and adaptive immune functions and inflammatory responses. NF-κB induces the expression of pro-inflammatory genes, participates in inflammasome regulation, and regulates the survival, activation, and differentiation of innate immune cells and inflammatory T cells. Deregulated NF-κB activation contributes to various inflammatory diseases. This review discusses the activation and function of NF-κB in inflammatory diseases and highlights therapeutic strategies based on NF-κB inhibition. The canonical and noncanonical NF-κB pathways are involved in different aspects of immune responses, with the canonical pathway being more extensively studied. NF-κB is involved in the induction of pro-inflammatory cytokines, chemokines, and inflammatory mediators in innate immune cells, as well as in the differentiation and effector function of inflammatory T cells. NF-κB also regulates inflammasome activation, which is crucial for the initiation and development of inflammatory diseases. Targeting NF-κB signaling represents an attractive approach for treating inflammatory diseases, with several categories of inhibitors being developed. However, the balance between efficacy and safety must be carefully considered, as NF-κB is also essential for maintaining normal immune responses and cell survival.