Therapeutic vaccination could become an important modality to fight cancer. Efficacious immune responses against cancer cells have to be directed simultaneously against multiple epitopes belonging to tumor-associated antigens and will require the involvement of both CD4(+) and CD8(+) cells as well as antibodies. The inoculation of a nucleic acid coding for a protein antigen by means of intradermal or intramuscular injection is a simple and cheap approach to induce an immune response against a target antigen. For long time, however, clinical translation of this concept has suffered from the poor immunogenicity of plasmid DNA vaccines in larger species. An emerging technology potentially capable of overcoming these limitations is in vivo electroporation. In this review, we report recent data showing initial evidence of immunogenicity by gene-electro-transfer in the clinic and discuss how new vector development combined with in vivo electroporation will allow nucleic acid vaccination to become a robust approach to fight cancer.