The concept of antisense technology is elegant but misleadingly simple. Short oligodeoxynucleotides (ODNs) complementary to a target messenger RNA form DNA-RNA hybrids by Watson-Crick base pairing rules, and interfere with expression of the encoded protein. The potential sequence specificity of antisense ODNs makes them attractive as molecular drugs in the treatment of human diseases. The skin is readily accessible and, in theory, is therefore suitable for application of antisense ODNs. Targeted and selective inhibition of keratinocyte gene expression in human epidermis could be an efficient and safe pharmacological approach in a number of skin diseases. Based on recent studies from our group and others, in this review we present our view on the usefulness of antisense ODN technology in skin for the modulation of gene expression related to skin diseases. It has become clear from these studies that practising antisense technology requires careful experimentation and critical data interpretation. Although the antisense technique was applied with success in some skin model systems, we feel that the technology is still in its infancy. The basic questions have been answered, but there are still many more that need to be addressed.