Neuroinflammatory processes seem to play a pivotal role in various chronic neurodegenerative diseases, characterized also by the pathogenetic accumulation of specific protein aggregates. Several of these proteins have been shown to be substrates of transglutaminases, calcium-dependent enzymes that catalyze protein crosslinking reactions. However, it has recently been demonstrated that transglutaminase 2 (TG2) may also be involved in molecular mechanisms underlying inflammation. In the central nervous system, astrocytes and microglia are the cell types mainly involved in the inflammatory process. This review is focused on the increases of TG2 protein expression and enzyme activity that occur in astroglial, microglial and monocyte cell models in response to inflammatory stimuli. The transcription factor NF-κB is considered the main regulator of inflammation, being activated by a variety of stimuli including calcium influx, oxidative stress and inflammatory cytokines. Under these conditions, the over-expression of TG2 results in the sustained activation of NF-κB. Several findings emphasize the possible role of the TG2/NF-κB activation pathway in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Although further studies are needed to characterize the TG2/NF-κB cross-talk in monocytes/macrophages/microglia within the central nervous system, some results show that TG2 and NF-κB are co-localized in cell compartments. Together, evidence suggests that TG2 plays a role in neuroinflammation and contributes to the production of compounds that are potentially deleterious to neuronal cells.