Many reports have shown that the expression of transglutaminase 2 (TG 2) is increased in inflammatory diseases. Although during the last several decades multiple physiological roles for TG 2 have been demonstrated in various cell types, its role in the inflammatory process is not yet clear. TG 2 is a crosslinking enzyme that is widely used in many biological systems for tissue stabilization purposes and immediate defense against injury or infection. Aberrant activation of TG 2 activity in tissues contributes to a variety of diseases including neurodegenerative diseases, autoimmune diseases, and cancers. In most cases, TG 2 appears to form an inappropriate protein aggregate that may be cytotoxic enough to trigger inflammation and/or apoptosis. In some cases, such as celiac disease and rheumatoid arthritis, TG 2 is also associated with the pathogenic progression, as well as in the generation of autoantibodies. Recently, we discovered that increased TG 2 activity triggers NF-κB activation without I-κBα kinase signaling. TG 2 induces the polymerization of I-κBα rather than stimulating I-κBα kinase. This polymerization of I-κB results in the direct activation of NF-κB in various cell lines. We also found that TG inhibition reverses NF-κB activation. Interestingly, this coincides with the reversal of inflammation in conjuctivitis models by treatment with TG 2 inhibitors. Here, I introduce a new role for TG 2 as a signal modulator, which may suggest a new paradigm for the inflammatory process.