The absence or loss of skin, because of the resulting drain of fluids and protein and because of the risk of invasive infection, requires wound closure with a skin substitute. Split-thickness skin graft is the gold standard for skin substitutes. Human cadaver allografts are the ideal temporary skin substitute, and their life can be prolonged by immunosuppression in the recipient. The potential for transmission of human immunodeficiency virus infections from these grafts limits their use. Epidermis can be replaced with tissue-cultured autogenous keratinocyte sheets. Several groups have used these grafts in patients successfully. Recent evidence indicates that the new epidermis directs the differentiation of the subjacent collagen tissue into an architecture resembling a papillary and reticular dermis. Several methods are being evaluated for the direct replacement of the dermis, including cadaver dermis, collagen-GAG matrices, and fibroblast-impregnated collagen gels. Clinically useful advances in skin substitutes have been made in the last decade, and these advances will lead to the answer to the problem of missing skin.