Skin has evolved to protect not only by acting as a physical barrier, but also by its role in our powerful immune system. As a frontline of the hosts defense against pathogens, skin is well equipped for immune surveillance. For example, compared to many other tissues, the epidermis of the skin contains a high population of Langerhans cells, which are very potent immature dendritic cells. Thus, targeting antigens to the skin epidermis should be able to efficiently induce strong immune responses. However, the forbidden barrier posed by the stratum corneum layer of the epidermis prevents effective entrance of antigens into the epidermis. Nevertheless, non-invasive immunization onto the skin has proven in the last several years to be a viable immunization modality. DNA vaccine is a vaccine made of bacterial plasmid DNA encoding an antigen of interest. Upon uptake of the plasmid, host express and process the encoding antigen, and then mount immune responses against it. DNA vaccine is advantageous over many other types of vaccines. The feasibility of noninvasive immunization onto the skin with DNA vaccine has been confirmed. Although the potency of the immune response has proven to be weak, many skin stratum corneum disrupting chemical and physical approaches and DNA vaccine carriers/adjuvants that significantly enhance the resulting immune response have been reported. In addition, research on elucidating the mechanism of immune induction from non-invasively, topically applied DNA vaccine has also been carried out. With further improvement and optimization, non-invasive immunization onto the skin with DNA vaccine should be able to elicit reliable and efficacious immune response to a variety of antigens.