Celiac disease (CD) is triggered by the consumption of gluten-containing cereals to which patients mount a T-lymphocyte and antibody response in both immunoglobulin A and immunoglobulin G classes coupled with autoantibody production against self-proteins, predominantly type-2 (tissue) transglutaminase (TG2). TG2 autoantibodies are biologically active and bind to their target protein in the patients’ tissues, including the gut and extraintestinal tissues. This peculiar systemic anti-TG2 reaction is dependent on the presence of dietary gluten and stops after its elimination. As both anti-TG2 and anti-gliadin antibodies are activity markers, their detection is valuable for the disease recognition and therapy monitoring. High concentrations of serum anti-TG2 antibody positivity supported by highly specific positivity for endomysial antibodies became the critical component of celiac disease diagnosis, although serum antibodies as indirect markers have limitations and are not able to replace histology analysis in all cases. Studies focusing on tissue-bound antibodies may further improve our understanding of their role.