Inflammation is a pathological hallmark associated with bacterial and viral infections, autoimmune diseases, genetic disorders, obesity and diabetes, as well as environmental stresses including physical and chemical trauma. Among numerous proteins regulating proinflammatory signaling, very few such as Protein kinase R (PKR), have been shown to play an all‐pervading role in inflammation induced by varied stimuli. PKR was initially characterized as an interferon‐inducible gene activated by viral double‐stranded RNA with a role in protein translation inhibition. However, it has become increasingly clear that PKR is involved in multiple pathways that promote inflammation in response to stress activation, both dependent on and independent of its cellular protein activator of PKR (PACT). In this review, we discuss the signaling pathways that contribute to the initiation of inflammation, including Toll‐like receptor, interferon, and RIG‐I‐like receptor signaling, as well as inflammasome activation. We go on to discuss the specific roles that PKR and PACT play in such proinflammatory signaling, as well as in metabolic syndrome‐ and environmental stress‐induced inflammation. Inflammation is the body's protective response against injury, infection, and stress. Several cellular proteins play specific roles in the inflammatory response to particular stimuli. Interestingly, some proteins such as protein kinase R (PKR) and the protein activator of PKR (PACT) play diverse roles in mediating the cellular inflammatory response to various stimuli. This review summarizes the current knowledge on the diverse roles of the proteins PKR and PACT in inflammation and their implications in select diseases.