Bromodomains are structural motifs that bind to acetylated N-ε-lysine residues on histones and transcription factors. Epigenetic proteins can contain bromodomains which are responsible for recognizing sequence-specific post-translational acetylation patterns, promoting downstream gene transcription through reversible and dynamic processes. These bromodomain-containing proteins also form transient interactions with additional members of the transcriptional machinery to regulate aberrant gene expression and promote inflammation, cancer, and viral replication. The bromodomain and extra-terminal (BET) family has been a target of interest in drug discovery due to the strong phenotypic effects that are observed upon disruption. The BET family consists of four separate proteins (BRD2, 3, 4, and testis-specific BRDT,). In the context of inflammation, BRD2 and BRD4 localize at super-enhancers, enriched in the epigenetic activating mark H3K27Ac, and recruit positive transcription elongation factor b (P-TEFb). These large co-activator complexes can initiate transcriptional elongation, where BRD4 engages P-TEFb through its C-terminal domain. In BET-driven inflammatory models, extracellular subunit of NF-κB by p300, resulting in a direct interaction between NF-κB and BRD4 (Figure ). In inflammatory signaling, both NF-κB and BRD4 are necessary for inducing the expression of inflammatory cytokines and chemokines, such as IL-6, CCL2, CXCL1, and CXCL8. The expression of these cytokines and chemokines directly promotes neutrophil infiltration and damaging effects in diverse tissues. From a therapeutic standpoint, BET inhibitors can disrupt interactions with acetylated NF-κB in LPS-stimulated macrophages, disrupting downstream signaling. As such, the BET proteins, and their interactions with acetylated NF-κB, represent key upstream targets for drug discovery in inflammation.