NF-kappaB transmits signals from the cell surface to the nucleus. Signaling through cell surface receptors to activate NF-kappaB and mitogen-activated protein kinases through adaptor molecules is of critical importance to survival and activation of all cells in the body, including those regulating innate and adaptive immunity. As such, NF-kappaB is a key signaling component in autoimmunity and an attractive target for autoimmune disease therapy. However, given its global importance, targeting NF-kappaB tends to be immunosuppressive. In this review, the authors discuss the roles played by NF-kappaB in autoimmunity, drugs which target it, and complexities which need to be addressed to improve the use of NF-kappaB as a target. Finally, the authors highlight some novel approaches that are likely to be important in the next generation of NF-kappaB therapies.