Pemphigus is caused by IgG autoantibodies directed against desmogleins (Dsg), keratinocyte desmosomal glycoproteins belonging to the cadherin family. Anti-Dsg IgG antibodies interfere with adhesive of desmogleins, causing the detachment of keratinocytes (acantholysis). In our laboratory, an alternative approach to pemphigus immunotherapy has been tested. The peptidic vaccine approach is based on the identification of peptidic epitopes within the sequence of known autoantigens and the use of such peptides to evoke tolerance (as in autoimmune disease) or to boost effector immune mechanisms (as in immunotherapy of tumors). This approach shows that in silico mapping of low-similarity sequences may add to the prediction of peptide immunogenicity. Thus peptide immunotherapy for pemphigus deserve further investigations before joining the therapeutic arsenal for pemphigus and related disorders.