Nuclear factor kappaB (NF-kappaB) is regarded as a key regulator of inflammation; hence, several inflammatory diseases result from deregulation of NF-kappaB signaling. There is, however, also increasing evidence for a preponderant role of NF-kappaB in tumor development and progression. Constitutive activation of NF-kappaB activity by signaling defects, mutations or chromosomal rearrangements can be found in a wide variety of cancers. Additionally, a causal link between inflammation and cancer has been noted, which makes NF-kappaB an interesting target for development of both anti-inflammatory and anti-cancer therapeutics. Here, we review current knowledge of NF-kappaB signal transduction, focusing on the regulation of its transcriptional activity by post-translational modification of the NF-kappaB subunits.