Nuclear factor kappaB (NF-kappaB) is an inducible transcription factor that tightly regulates the expression of a large cohort of genes. As a key component of the cellular machinery NF-kappaB is involved in a wide range of biological processes including innate and adaptive immunity, inflammation, cellular stress responses, cell adhesion, apoptosis and proliferation. Appropriate regulation of NF-kappaB is critical for the proper function and survival of the cell. Aberrant NF-kappaB activity has now been implicated in the pathogenesis of several diseases ranging from inflammatory bowel disease to autoimmune conditions such as rheumatoid arthritis. Systems governing NF-kappaB activity are complex and there is an increased understanding of the importance of nuclear events in regulating NF-kappaB's activities as a transcription factor. A number of novel nuclear regulators of NF-kappaB such as IkappaB-zeta and PDZ and LIM domain 2 (PDLIM2) have now been identified, adding another layer to the mechanics of NF-kappaB regulation. Further insight into the functions of these molecules raises the prospect for better understanding and rational design of therapeutics for several important diseases.