A wide spectrum of diseases of the skin are manifested as a blistering process. Blistering may occur as a secondary event associated with viral or bacterial infections of the skin, eg, herpes simplex and impetigo, or with local injury of the skin, eg, burns, ischemia, and dermatitis. In other diseases, blistering of the skin occurs as a primary event and is associated with tissue injury and fluid accumulation within a specific layer of the skin: intraepidermal, dermal-epidermal junction, or subepidermal. Blister formation in this latter group of diseases is due to either genetic mutation or an autoimmune response. Genodermatoses associated with blisters are typically manifested in the neonate, whereas the autoimmune blistering disorders are acquired and usually expressed later in life. Recent advances have uncovered the relevance of the keratinocyte cytoskeleton, the desmosome, the hemidesmosome, and extracellular matrix proteins in blister formation. A pathogenetic classification of blistering diseases is presented.