DNA vaccines represent a new and promising technology that uses DNA to encode the antigen(s) of interest, instead of inoculating with attenuated or inactivated microbes or isolated antigens. Antigen is produced within the transfected cells minaicking a real life viral infection. This vaccine modality has been shown to elicit strong cellular immune responses and is promising for treating diseases where traditional vaccine approaches have failed. In spite of promising results in small animal models, DNA vaccines have so far proven less potent in human clinical trials. In this review we provide a general overview on the mechanisms of action for DNA vaccines, discuss potential benefits of traditional vaccine approaches and review current strategies for improving the immunogenicity of DNA vaccines to enable the successful transfer of the technology can be successfully transferred from mice to men.