In the past 10 years, impressive progress has been made on how the NF- kappaB transcription factor is regulated and how diverse signals frequently use ubiquitin-dependent mechanisms to activate NF- kappaB. Many of the signal transducers and regulatory enzymes have been identified and their essential roles in NF- kappaB regulation revealed through genetic analyses in mice. More recent work highlights the importance of NF- kappaB in innate immune signaling by cell surface Toll-like receptors and cytosolic Nod-like receptors. Although current research clearly implicates NF- kappaB in diabetes, inflammatory diseases and cancer, a challenge for the future will be to reveal the precise molecular and cellular mechanisms of NF- kappaB dysfunction in disease. The realization that NF- kappaB activity is regulated by kinases and ubiquitin modifying enzymes presents multiple opportunities for therapeutic intervention. In addition to highlights from basic research, results from clinical trials using IKK and other NF- kappaB inhibitors are expected to be presented at this meeting.