The IκB kinase (IKK) complex is involved in transcriptional activation by phosphorylating the inhibitory molecule IκBα, a modification that triggers its subsequent degradation, enabling activation of nuclear factor kappa B (NF-κB). Importantly, recent reports indicate that multiple cytoplasmic and nuclear proteins distinct from the NF-κB and IκB proteins are phosphorylated by the catalytic subunits of the IKK complex, IKKα or IKKβ. Here, I describe how IKK subunits can have crucial roles in allergy, inflammation and immunity by targeting proteins such as SNAP23 and IRF7, but also in cancer by phosphorylating key molecules such as p53, TSC1 and FOXO3a through NF-κB-independent pathways. Thus, these recent findings considerably widen the biological roles of these kinases and suggest that a full understanding of the biological roles of IKKα and IKKβ requires an exhaustive characterization of their substrates.