Novel therapeutic strategies can be envisioned based on altering the expression level of target genes involved in cellular processes and disease progression; however, our ability to efficiently manipulate gene expression is limited. Non-viral-based gene therapy provides a relatively safe approach to increase or decrease the expression of a specific gene using DNA or antisense sequences; however, synthetic systems are required to direct plasmids and oligonucleotides to a specific tissue and to enhance cellular uptake and intracellular trafficking. Numerous materials are being developed that interact with DNA to enhance its properties (e.g. stability, charge density) and thus direct its biodistribution and facilitate cellular interactions. The development of synthetic delivery systems to manipulate gene expression efficiently is a powerful tool that will ultimately lead to novel therapeutic strategies for the treatment of numerous disorders.