Interest in DNA immunization of animals continues, despite the fact that immune responses induced by DNA vaccines are generally lower than those elicited by conventional vaccines. In attempts to enhance the immune response to DNA vaccines, individuals have tried a variety of immune modulators, cytokines, and costimulatory molecules, but these only boost immune responses marginally. These results clearly demonstrate that the major challenge to improving DNA-based vaccines is to improve the transfection efficiency. Gene gun and electroporation can increase transfection and improve immune responses significantly, but these technologies have not yet advanced to the stage of routine use in livestock. Hopefully, transfection efficiency can be increased further in a user-friendly manner to ensure that the benefits of using DNA vaccines become a reality.