Topical DNA vaccines have been shown to elicit both broad humoral and cellular immune response in vivo. The skin is an attractive site for the delivery DNA antigens for DNA vaccination. However, due to skins barrier properties, the penetration of DNA and the applications of topical vaccination are limited. To improve permeability of stratum corneum and the potency of topical DNA vaccines, efficient delivery systems are needed. Topical vaccination has been achieved using topical application of naked DNA with or without tape stripping and DNA/lipid based complex such as liposomes, niosomes, Transfersomes®, or microemulsion. All methods resulted in significant enhancement in humoral and cellular immune response over naked DNA alone. To develop more cost-effective and needle free vaccines, skin targeted immunizations are required. This overview focuses on the comparison of the potency of topical DNA vaccine between naked DNA and DNA-lipid based complex.