Although the field of gene delivery is dominated by viral vectors and synthetic polymeric or lipid gene carriers, natural polymers offer distinct advantages and may help advance the field of non-viral gene therapy. Natural polymers, such as chitosan, have been successful in oral and nasal delivery due to their mucoadhesive properties. Collagen has broad utility as gene activated matrices, capable of delivering large quantities of DNA in a direct, localized manner. Most natural polymers contain reactive sites amenable for ligand conjugation, cross-linking, and other modifications that can render the polymer tailored for a range of clinical applications. Natural polymers also often possess good cytocompatibility, making them popular choices for tissue engineering scaffolding applications. The marriage of gene therapy and tissue engineering exploits the power of genetic cell engineering to provide the biochemical signals to influence proliferation or differentiation of cells. Natural polymers with their ability to serve as gene carriers and tissue engineering scaffolds are poised to play an important role in the field of regenerative medicine. This review highlights the past and present research on various applications of natural polymers as particulate and matrix delivery vehicles for gene delivery.