Ubiquitination has emerged over the years as the most sophisticated way to modify proteins to affect their fate and function. In particular, it has been reported to be instrumental in regulating several steps of the NF-kappaB signalling pathway which controls inflammation, immunity, adhesion and cell survival. Integrating ubiquitination into NF-kappaB activation requires the regulatory subunit of IKK, NEMO, which not only displays affinity for polyubiquitin chains, but is also posttranslationally modified by a complex set of reactions involving ubiquitin. Here, we examine how studies of the NEMO/ubiquitin relationship have provided novel insights into the IKK activation process and have uncovered molecular mechanisms that should represent in the future attractive targets for specifically modulating NF-kappaB function.