Vaccines have significantly improved human health through decreasing morbidity and mortality associated with infectious diseases. Through the use of vaccines, we have seen the eradication of Small Pox and the control of numerous other diseases which once crippled the society. However, older vaccine technologies have not been successful in tackling many remaining infectious diseases including Human Immunodeficiency Virus (HIV), Malaria, Tuberculosis (TB), emerging diseases or therapeutically impacting cancer. Due to the complexity of these targets, novel vaccine platforms are needed. DNA vaccines were first reported in the early 1990s and demonstrated significant success in small animals. However, due to their lack of robust immunogenicity in large animals and human subjects, excitement was quickly tempered. After years of optimizations and improvements, DNA vaccines can now generate responses as high or higher than other vaccine platforms in these species. Here we explore some of the strength of DNA vaccine technology to improve vaccine-induced responses further. First, due to the ease of production and ability to formulate multiple plasmids into a single immunization, we explore the relationship between vaccine breadth and the coverage of induced responses. Formulations of multiple plasmids encoding the HIV-1 surface protein, Envelope, were able to induce superior responses compared to a single plasmid formulation. These responses were further improved by including small clusters of plasmids, limiting the diversity within a single immunization. We also explore the use of plasmid encoded immune adjuvants to enhance or tailor the vaccine responses. Two sets of adjuvants, mucosal chemokines and various forms of CD40L, display a range of adjuvanting effects and can increase protection against challenge. Overall, these improvements in DNA vaccine performance will progress the translational development of new studies aimed at impacting important, however, difficult infectious diseases.