In order for genetic medicines to become viable commercial products, the active form of the drug (e.g., DNA) must be able to reach the site of action and remain there long enough to accomplish its intended function. Encapsulation of plasmid DNA into biodegradable microspheres is one approach towards solving this challenge. This review describes the primary methods for satisfactorily entrapping intact DNA into biodegradable polymeric matrices. In particular, the materials, processes, and equipment required for each encapsulation method are described in detail. The resulting microspheres could be used for parenteral, oral, and inhalation therapy.