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Innate immune responses rely on rapid and precise gene regulation mediated by accessibility of regulatory regions to transcription factors (TFs). In natural killer (NK) cells and other innate lymphoid cells, competent enhancers are primed during lineage acquisition, and formation of de novo enhancers characterizes the acquisition of innate memory in activated NK cells and macrophages. Here, we investigated how primed and de novo enhancers coordinate to facilitate high-magnitude gene induction during acute activation. Epigenomic and transcriptomic analyses of regions near highly induced genes (HIGs) in NK cells both in vitro and in a model of Toxoplasma gondii infection revealed de novo chromatin accessibility and enhancer remodeling controlled by signal-regulated TFs STATs. Acute NK cell activation redeployed the lineage-determining TF T-bet to de novo enhancers, independent of DNA-sequence-specific motif recognition. Thus, acute stimulation reshapes enhancer function through the combinatorial usage and repurposing of both lineage-determining and signal-regulated TFs to ensure an effective response. • Inducible high-density p300 enhancers form in proximity to highly dynamic genes • Strong transcriptional induction occurs with both primed and non-primed enhancers • De novo enhancers form in vivo during NK cell response to Toxoplasma gondii infection • STATs initiate chromatin opening with T-bet redeployment to non-canonical sites During development, innate lymphocytes acquire defined sets of primed enhancers facilitating the rapid immune response. In this issue of Immunity , Sciumè et al. delineate the epigenetic changes occurring during acute NK cell activation, revealing the formation of de novo enhancers and repurposing of both lineage-determining and signal-regulated transcription factors. [ABSTRACT FROM AUTHOR]