The most characteristic feature of pemphigus is a loss of cohesion between keratinocytes, resulting in formation of blisters and erosions on the mucosal membranes and the skin. Identification of circulating antibodies which bind to desmogleins (Dsg), transmembrane proteins involved in assembly of the desmosomes, led to the immediate realization that these antibodies may be pathogenic by interfering with desmosomal function. Despite extensive experimental evidence documenting the presence of the anti-Dsg response, its pathogenic relevance is still debated. At the current stage of the knowledge it seems likely that anti-Dsg imunoglobulins may play a role in pemphigus via interference with cellular Dsg trafficking and by activation of specific signalling pathways rather than by simple interference with desmosomal adhesion.