Transglutaminase 2 (TGM2), also known as tissue transglutaminase, is a ubiquitously expressed enzyme that catalyzes calcium-dependent post-translational modifications of proteins, including crosslinking and deamidation. It plays diverse roles in cellular processes such as apoptosis, signaling, and extracellular matrix organization. In autoimmune contexts, TGM2 has gained prominence as a target of autoantibodies in celiac disease. Here, TGM2 deamidates gluten-derived gliadin peptides, enhancing their immunogenicity and triggering an adaptive immune response. Anti-TGM2 IgA antibodies are hallmark serological markers for celiac disease diagnosis, with high specificity and sensitivity. These autoantibodies also contribute to disease pathology by forming immune complexes that may damage intestinal tissues. Beyond celiac disease, TGM2 dysregulation is linked to cancer progression, fibrosis, and neurodegenerative disorders. In oncology, elevated TGM2 expression correlates with metastasis, drug resistance, and poor prognosis, spurring interest in therapeutic antibodies targeting TGM2. However, challenges remain due to TGM2's dual enzymatic and signaling functions, potential off-target effects, and isoform complexity. Research continues to explore TGM2 antibody applications in diagnostics, disease monitoring, and targeted therapies, balancing clinical utility against mechanistic understanding of TGM2's multifaceted biology.