Gene transfer to the skin is essential for correcting genetic disorders and studying skin biology. Previous attempts at in vivo gene transfer have employed replication-deficient adenovirus injected subcutaneously and plasmid DNA propelled by a gene gun. In this report, we used mouse skin as a model and evaluated the efficiency of these two methods. Using the luciferase reporter gene, we found that adenovirus injected subcutaneously transduced primarily cells in the dermis. However, particle bombardment of skin by gene gun delivered the reporter gene mainly into the epidermis. When mouse skin was bombarded with a DNA construct expressing human TGF-alpha, the epidermis of the treated mice showed localized epidermal acanthosis and hypergranulosis, which resembled the histological phenotype of previously described transgenic mice overexpressing TGF-alpha in the epidermis. These results suggest that the gene gun may be an effective tool for epidermal gene transfer and could be potentially useful in determining in vivo effects of growth factors and cytokines on the epidermis.