Post-translational modifications are associated with certain autoimmune diseases. For example, in the initial steps of coeliac disease (CD), transglutaminase type 2 (TG2) catalyzes a post-translational deamidation of specific glutamine residues in dietary gluten, resulting in antibodies against both modified gliadin and against TG2. Anti-TG2 has become a specific biomarker for CD. In rheumatoid arthritis (RA), the presence of antibodies against citrullinated peptides (ACPA) characterizes a distinct subset of this inflammatory disorder. Moreover, antibodies against the enzyme that catalyzes the citrullination (peptidylarginine deiminase; PAD) are found in RA. Their relation to disease severity indicates a possible pathogenetic role. Thus, in two major autoimmune diseases (CD and RA), antibodies are present against a post-translationally modified substrate and against the calcium-dependent thiol-enzyme (TG2 and PAD, respectively) responsible for the modification. This review highlights the similarities between the TGs and the PADs and their putative pathogenetic roles in autoimmune diseases. Possible mechanisms of the effects of cigarette smoking and alcohol consumption on RA are discussed. By reflecting the progress in CD, the pathogenesis of ACPA-positive RA can be hypothesized where expression and regulation of PADs play significant roles. Indeed, autoimmune diseases should be studied collectively as well as individually. The new insight may lead towards innovative pharmacotherapeutic principles.