Were there to be a crossroads through which all inflammatory signaling passed, controlling that junction would provide the ultimate therapeutic target for rheumatoid arthritis and many, if not all, autoimmune diseases. It now seems likely that no single cytokine or cytokine family represents such a crucial nexus. However, there is reason to believe that there may be an intracellular bottleneck that does: the family of NF-κB proteins. This family of proteins allows cytokine–receptor signals to enter the nucleus and either enhance or suppress the transcription of many genes involved in inflammation and in cellular survival itself. The same set of proteins is also involved in apoptosis and likely in carcinogenesis. The delicate choreography of control systems, balancing the effects of NF-κB proteins on the multiple DNA sites that are targeted, is also a prime target for specific therapies. Moreover, the NF-κB system interdigitates with other intracellular systems, eg, kinases, ubiquitin-associated protein degradation, that are critical to the normal function of cells, involved in homeostasis and inflammation, in autoimmune diseases and malignancy.