The N-terminal bromodomains (D1 and D2) of the BET proteins (Figure ) provide additional mechanisms for protein-protein interactions, the details of which still remain unclear. Developing selective inhibitors targeting a single BET bromodomain is challenging, as the tandem bromodomains of each of the BET proteins retain high sequence similarity including 75% similarity across all D1s, and 42% D1 vs D2s. Additionally, complete inhibition of all eight BET bromodomains masks the discrete function of each of these domains, limiting progression to clinical applications. Early pan-BET bromodomain inhibitors, such as (+)-JQ1 and I-BET151 (Figure ), were shown to attenuate inflammation under various conditions, indicating that BET inhibition is a viable method for the treatment of diverse inflammatory diseases. However, pan-BET inhibitors in the clinic, such as ABBV-075, have faced significant hurdles due to on-target dose-limiting toxicity, including thrombocytopenia and gastrointestinal adverse effects. Despite these limitations, BET inhibitors have been used to probe diverse inflammatory pathways including cardiac inflammation, inflammation from titanium nanoparticle exposure, and β-cell inflammation in diabetes. In the liver, a role for BET proteins has been identified in inflammation and fibrosis of metabolic dysfunction-associated steatohepatitis and alcoholic hepatitis etiologies. However, a general mechanism has yet to arise; in some cases pan-D2 inhibition is sufficient to reduce inflammation, while in others either BRD4 or both BRD4 and BRD2 function were necessary to regulate inflammatory signaling. Such divergent biology necessitates more focused studies involving BET proteins for each disease indication.