DNA vaccines represent a potentially promising approach for antigen-specific immunotherapy. Advances in our knowledge of the adaptive immune system have indicated that professional antigen-presenting cells, especially dendritic cells (DCs), play a key role in the generation of antigen-specific immune responses. Thus, the modification of the properties of DCs represents an important strategy for enhancing the potency of DNA vaccines. This review discusses strategies to increase the number of antigen-expressing DCs, enhance antigen expression, processing and presentation in DCs, promote the activation and function of DCs, and improve DC and T-cell interaction, in order to optimize DNA vaccine-elicited immune responses. Continuing progress in our understanding of DC and T-cell biology serves as a foundation for further improvement of DNA vaccine potency, which may lead to future clinical applications of DNA vaccines for the control of infectious diseases and malignancies.