Innate immune responses are an essential defence against infection but are also a key factor in chronic inflammatory disease. The consequences of inappropriate or unchecked inflammation necessitates the tight control of how and when innate immune cells respond to potential threats. The NF-ĸB family of transcription factors are master-regulators of the immune response and control the expression of key mediators of inflammation including cytokines. We have utilised CRISPR/Cas9 techniques to investigate the role of NF-ĸB phosphorylation in regulating the transcriptional responses of activated macrophages. The data identify a remarkable gene specific role for individual sites of phosphorylation and provide compelling evidence of transcriptional programming by NF-ĸB phosphorylation. The ability of the innate immune system to discriminate between stimuli that pose little danger and those that threaten the host is a key determinant of human health. I will also present our recent and unexpected finding that TPL-2 (MAP3K8), a key activator of the MAPK pathway in innate immune cells, is regulated in the nucleus by the NF-ĸB co-factor BCL-3. BCL-3 promotes TPL-2 degradation in the nucleus and thereby limits the duration and strength of MAPK responses in activated macrophages. The concentration of microbial-associated molecules that activates an innate inflammatory response is determined by the activation threshold of MAPK signalling pathways. Regulation of nuclear TPL-2 by BCL-3 sets the MAPK activation threshold and controls the cellular decision to respond to inflammatory stimuli. This represents a novel and regulatable mechanism that is used by cells to distinguish between threats that should be tolerated and those that require a strong inflammatory response.