Determination of the correct diagnosis and subclassification of inherited and acquired forms of epidermolysis bullosa (EB) can be exceedingly challenging because the clinical morphologic findings and routine histology are frequently nonspecific. The most precise means of diagnosing inherited EB involves the assessment of a combination of ultrastructural and antigenic features by transmission electron microscopy, immunofluorescence antigenic mapping, and EB-related monoclonal antibody studies. Acquired EB can usually be diagnosed by split skin indirect or direct immunofluorescence. When necessary, immunoelectron microscopy, immunoprecipitation, and immunoblot can be used.