In common acquired skin disorders with a polygenic background such as psoriasis, a linear or otherwise segmental arrangement may sometimes be noted. The segmental involvement tends to be rather severe and may be associated with milder, nonsegmental lesions of the same disorder. Such cases may be best explained by an early postzygotic event in the form of loss of heterozygosity involving one of the genes that predispose to the disorder. The following pertinent examples are reviewed in this article: psoriasis vulgaris, pustular psoriasis, atopic dermatitis, lichen planus, systemic lupus erythematosus, pemphigus vulgaris, vitiligo, graft-versus-host disease, granuloma annulare, erythema multiforme, and drug eruption to ibuprofen. Such cases should not be categorized as a “type 2 segmental manifestation” because this term exclusively applies to monogenic traits, whereas in polygenic disorders the more descriptive term “superimposed segmental manifestation” seems appropriate. The concept of early loss of heterozygosity offers a plausible explanation as to why: the segmental involvement tends to appear at a rather young age and often precedes the development of milder, nonsegmental lesions of the same disorder; the segmental lesions are notoriously difficult to treat; and family members may show the disorder in its nonsegmental form. On the other hand, the theory of isolated versus superimposed segmental manifestation may help to elucidate the origin of polygenic skin disorders at the molecular level.