Nucleic acid vaccines represent one of the most revolutionary breakthroughs in contemporary vaccinology by providing unprecedented speed, versatility, and scalability. This chapter offers a broad review of DNA and RNA vaccine technologies from view point of historical evolution of these platforms from primitive concept to mass vaccination under the conditions of COVID-19 pandemic. DNA vaccines act by transcribing antigens from a plasmid in the nucleus, while RNA vaccines deliver mRNA directly into the cytoplasm for immediate translation and thus do not need to enter the nucleus. Clinical breakthroughs—namely the DNA-based vaccine in India called ZyCoV-D, plus mRNA vaccines such as those developed by Pfizer-BioNTech and Moderna that have been deployed worldwide 1—show that nucleic acid immunization has real-world promise. Besides infectious diseases, case reports showcase their growing utility for cancer therapy, immune modulation, and veterinary medicine applications. The chapter also addresses the immunological foundation of nucleic acid vaccines, involving strong humoral, cellular, and innate immune stimulation. Recent advances, such as self-amplifying RNA, circular RNA, and microneedle delivery systems overcome the issues of stability, dosage, and availability. Although there are challenges of logistics, delivery and public perception, continuous technological advances make nucleicacid vaccines indispensable for future pandemic preparedness as well as personalized medicine.