Loss of heterozygosity (LOH) is a genetic mechanism by which a heterozygous somatic cell becomes either homozygous or hemizygous because the corresponding wild-type allele is lost. LOH has today been recognized as a major cause of malignant growth. This article gives a comprehensive review of skin disorders in which an origin from LOH has been either documented at the molecular level or postulated on the basis of clinical evidence. LOH has been shown to cause basal cell carcinoma, squamous cell carcinoma, and malignant melanoma, but this mechanism can likewise be taken as an important model to explain the origin of many other skin diseases such as benign hamartomas; type 2 segmental manifestation of autosomal dominant skin disorders; a pronounced segmental manifestation of acquired skin disorders with a polygenic background, superimposed on symmetric lesions of the usual type; paired mutant patches in the form of either allelic or nonallelic twin spotting; and the exceptional familial occurrence of some nevi, reflecting paradominant transmission. (J Am Acad Dermatol 1999;41:143-61.) Learning objective: At the completion of this learning activity, readers should be familiar with the mechanism of LOH and its general significance for the biology of plants, animals, and humans. Participants should understand that this mechanism plays a crucial role not only in cutaneous malignant growth but also in the development of benign skin disorders, and they should be able to examine such diseases with a prepared mind to gain a better understanding of their origin.