The NF-κB family of transcription factors plays crucial roles in the inflammatory processes in RA leading to cartilage and bone destruction. Keeping NF-κB activation under control can thus be very important for the design of specific therapeutics. The existence of multiple negative regulators ensuring a tight regulation of the NF-κB pathway, however, raises the question of the specific role of each of these regulators and the relationship between them. In addition, given the number of miRNAs in humans and the multiple mRNAs they target, intense complexity can be expected. How all these regulatory signals are themselves regulated will be an important question in order to clarify how NF-κB signalling is organised, and, more importantly, how this knowledge may lead to new treatments for inflammatory diseases such as RA.