Vaccination has been the most efficacious way to combat infectious diseases in human history. Nevertheless, there are still a variety of pathogens for which vaccines are urgently needed. In the last 25 years, DNA vaccines emerged as promising in prophylactic and therapeutic settings. However, despite all the practical advantages, DNA vaccines face challenges in inducing potent antigen specific immune responses and protection in humans. In the last years, rational approaches to improve the efficacy of DNA vaccines were developed and include: modifications of plasmid basic design, use of next-generation delivery methods, addition of adjuvants in the formulation, improvement in immunization protocols and even targeting to dendritic cells. In this review, we will explore the advances and hurdles involved in the development of more potent DNA vaccines.