A VARIETY OF SKIN diseases may present with the appearance of blisters (Table 22.1). The skin reacts with the formation of vesicles or larger bullae to a number of external physical, chemical, and biological insults. Adverse reactions to systemic or topically applied drugs occupy an important place in the differential diagnosis of blistering eruptions. Bullous lesions can also occur as a manifestation of systemic diseases, as is the case of the bullae seen in diabetic patients. Atypical blistering forms of several inflammatory dermatoses exist, such as bullous lichen planus, bullous morphea, or bullous mycosis fungoides. In all these cases, blistering lesions are infrequent and temporary, in contrast to a group of chronic cutaneous disorders referred to as “bullous dermatoses,” where vesiculobullous lesions are the main and characteristic clinical feature. Some bullous dermatoses are due to genetically determined loss of basic structural elements in the skin that maintain the cohesion between the keratinocytes in the epidermis, or between the epidermal layer and the dermis within the basement membrane zone (BMZ). The majority of bullous dermatoses, however, are acquired organ-specific autoimmune diseases in which the autoantibodies target structural proteins in the skin. These disorders constitute one of the major sources of morbidity and mortality in dermatology.