DNA vaccines are potentially important immunotherapeutic agents for combating infectious diseases and cancers. Continuing progress in our understanding of how professional antigen presenting cells (APCs) orchestrate immune responses has provided a framework from which to design effective DNA vaccines. Similarly, manipulation of DNA using advances in molecular biology technology has enabled implementation of novel DNA vaccine strategies. This review summarizes recent vaccine strategies that utilize intercellular and intracellular modification of professional APCs, including those involving plasmid delivery, intracellular processing of antigen and enhancement of APC interaction with T-cells.