Vaccination has eradicated smallpox and greatly decreased mortality and morbidity associated with a variety of viral and bacterial infectious diseases. However, conventional methodologies have failed to provide vaccines against many widespread deadly human diseases, among them HIV, malaria and cancer. Recombinant DNA vaccines have shown great promise in animal models in inducing protective immunity. In this review we will discuss their potential safe use in humans following recent advances in their use in animals, including non-human primates.