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The pleiotropic consequences of nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) pathway activation result from the combinatorial effects of the five subunits that form the homo- and heterodimeric NF-κB complexes. Although biochemical and gene knockout studies have demonstrated overlapping and distinct functions for these proteins, much is still not known about the mechanisms determining context-dependent functions, the formation of different dimer complexes and transcriptional control in response to diverse stimuli. Here we discuss recent results that reveal that the nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) (p105/p50) subunit is an important regulator of NF-κB activity in vivo. These effects are not restricted to being a dimer partner for other NF-κB subunits. Rather p50 homodimers have a critical role as suppressors of the NF-κB response, while the p105 precursor has a variety of NF-κB-independent functions. The importance of Nfkb1 function can be seen in mouse models, where Nfkb1(-/-) mice display increased inflammation and susceptibility to certain forms of DNA damage, leading to cancer, and a rapid ageing phenotype. In humans, low expression of Kip1 ubiquitination-promoting complex 1 (KPC1), a ubiquitin ligase required for p105 to p50 processing, was shown to correlate with a reduction in p50 and glioblastoma incidence. Therefore, while the majority of research in this field has focused on the upstream signalling pathways leading to NF-κB activation or the function of other NF-κB subunits, such as RelA (p65), these data demonstrate a critical role for NFKB1, potentially revealing new strategies for targeting this pathway in inflammatory diseases and cancer.