The nuclear factor-κB (NF-κB)/REL family of transcription factors has a central role in coordinating the expression of a wide variety of genes that control immune responses. There has been intense scientific activity in the NF-κB field owing to the involvement of these factors in the activation and regulation of key molecules that are associated with diseases ranging from inflammation to cancer. In this review, we focus on our current understanding of NF-κB regulation and its role in the immune system and inflammatory diseases. We also discuss the role of NF-κB proteins as potential therapeutic targets in clinical applications.