DNA vaccination is an attractive immunization method able to induce robust cellular immune responses in pre-clinical models. However, clinical DNA vaccination trials performed thus far have resulted in marginal responses. Consequently, strategies are currently under development to improve the efficacy of DNA vaccines. A promising strategy is the use of synthetic particle formulations as carrier systems for DNA vaccines. This review discusses commonly used synthetic carriers for DNA vaccination and provides an overview of in vivo studies that use this strategy. Future recommendations on particle characteristics, target cell types and evaluation models are suggested for the potential improvement of current and novel particle delivery systems. Finally, hurdles which need to be tackled for clinical evaluation of these systems are discussed.