Epidermal blister formation is the hallmark of three cutaneous autoimmune diseases: pemphigus foliaceous (PF), pemphigus vulgaris (PV) and bullous pemphigoid (BP). In PF and PV, blistering is due to acantholysis (cell-cell detachment) in the subcorneal and suprabasal epidermal layers, respectively, while BP is characterized by detachment of the basal epidermal cells from the underlying dermis. For several years, we have focused our research efforts on elucidating the pathogenic mechanisms operating in these bullous diseases. Early studies performed by our research group and others revealed that in all three diseases, the patients produce autoantibodies that bind to target antigens located on the surface of cells that are undergoing detachment. Thus it was hypothesized that these anti-epidermal autoantibodies played a role in initiating blister formation. We recognized that elucidating the normal mechanisms of epidermal cell-cell and cell-dermis adhesion would help us understand the abnormal epidermal cell detachment seen in these patients. We hypothesized that under normal conditions these adhesive mechanisms in the epidermis are complex and dynamic and mediated by the interaction of cell surface molecules unique to each layer of the epidermis. Also, we postulated that PV, PF and BP autoantibodies may cause cell detachment by impairing the function of their respective epidermal cell surfaces. Support for this hypothesis has come from recent studies which showed that PV and PF autoantibodies recognize distinct, yet related, desmosomal glycoproteins in the cadherin family of calcium-dependent adhesion molecules. The epidermal antigen in PV is desmoglein-3 (dsg3), while in PF it is desmoglein-1 (dsg1). These anti-epidermal autoantibodies have been shown to be pathogenic in passive transfer experiments. Neonatal mice injected with these antibodies develop intraepidermal blisters characteristic of the corresponding human disease. Autoantibodies in BP react with BP180 and BP230, two major components of the hemidesmosome, a cell structure involved in dermal-epidermal adhesion. Recent passive transfer mouse model studies performed in our laboratory have shown that anti-BP180 antibodies can induce subepidermal blistering in the experimental animals. Moreover, the pathogenic mechanism was shown to be dependent on complement activation and recruitment of neutrophils to the dermal-epidermal junction. In conclusion, desmosomal glycoproteins are the targets of autoimmune injury in PV and PF. The anti-epidermal autoantibodies may cause intraepidermal blisters by impairing the function of dsg1 and dsg3. In BP the hemidesmosome is the target. It appears that antiBP180 antibodies cause subepidermal blister formation by triggering a complement- and neutrophil-mediated inflammatory process.