Both DNA and mRNA can be used as vehicles for gene therapy. Because the immune system is naturally activated by foreign nucleic acids thanks to the presence of Toll-like Receptors (TLR) in endosomes (TLR3, 7, and 8 detect exogenous RNA, while TLR9 can detect exogenous DNA), the delivery of foreign nucleic acids usually induces an immune response directed against the encoded protein. Many preclinical and clinical studies were performed using DNA-based experimental vaccines. However, no such products are yet approved for the human population. Meanwhile, the naturally transient and cytosolically active mRNA molecules are seen as a possibly safer and more potent alternative to DNA for gene vaccination. Optimized mRNA (improved for codon usage, stability, antigen-processing characteristics of the encoded protein, etc.) were demonstrated to be potent gene vaccination vehicles when delivered naked, in liposomes, coated on particles or transfected in dendritic cells in vitro. Human clinical trials indicate that the delivery of mRNA naked or transfected in dendritic cells induces the expected antigen-specific immune response. Follow-up efficacy studies are on the way. Meanwhile, mRNA can be produced in large amounts and GMP quality, allowing the further development of mRNA-based therapies. This chapter describes the structure of mRNA, its possible optimizations for immunization purposes, the different methods of delivery used in preclinical studies, and finally the results of clinical trial where mRNA is the active pharmaceutical ingredient of new innovative vaccines.