Double-stranded RNA-dependent protein kinase (PKR) is implicated in inflammation and immune dysfunction through its regulation of mitogen-activated protein kinases, interferon regulatory factor 3, nuclear factor κB, apoptosis, and autophagy pathways. A study shows that PKR is also required for the activation of inflammasomes and the subsequent release of high-mobility group box 1 (HMGB1) protein, a proinflammatory cytokine. Thus, the cell stress kinase PKR has multifaceted roles in the regulation of inflammatory immune responses, and PKR and HMGB1 are attractive targets for inflammasome-associated diseases.