The pathogenesis of pemphigus vulgaris (PV) is a highly controversial, "hot" topic that has received considerable enrichment in recent years by both clinical and basic researchers. On the one hand, the classical view of desmogleins (Dsg) as main targets of this autoimmune disease is supported by the characterization of pathogenic anti-Dsg3 antibodies from both patients and animal models. On the other hand, fundamental doubt has been raised towards this monopathogenic view by several independent factors: (1) pemphigus lesions can be induced in Dsg3-knockout (KO) mice; (2) pemphigus sera contain multiple autoantibodies against different adhesion molecules and also cholinergic receptors; (3) experimental inhibition of PV IgG induced acantholysis can be obtained by interference with different signaling cascades regulating both calcium homeostasis and apoptosis; and (4) cholinergic agonists exhibit anti-acantholytic activity both in vitro and in vivo. The field is open for controlled clinical trials and further basic research to unfold the true story of the pemphigus enigma and provide the basis for a better treatment of pemphigus patients.