Bullous pemphigoid (BP) is a blistering skin disease characterized by an autoimmune response to 2 hemidesmosomal proteins within the dermal-epidermal junction, designated BP180 and BP230. While BP230 localizes intracellularly and associates with the hemidesmosomal plaque, BP180 is a transmembrane glycoprotein with an extracellular domain. Most BP patients have autoantibodies binding to an immunodominant region of BP180, the noncollagenous 16A domain (NC16A), which is located extracellularly close to the transmembrane domain of the protein. Autoreactive T and B cell responses to BP180 have been found in patients with BP. Passive transfer of antibodies to the murine BP180 ectodomain triggers a blistering skin disease in mice that closely mimics human BP. Lesion formation in this animal model depends upon complement activation, mast cell degranulation and accumulation of neutrophils and eosinophils. Patients' autoantibodies to BP180 induce dermal-epidermal separation in cryosections of human skin when co-incubated with leukocytes. The loss of cell-matrix adhesion is mediated by proteinases released by granulocytes. The increased knowledge of the pathophysiology of BP should facilitate the development of novel therapeutic strategies for this disease.