Gene and RNA interference therapies have significant potential for alleviating countless diseases, including many associated with the gastro-intestinal (GI) tract. Unfortunately, oral delivery of genes and small interfering RNA (siRNA) is very challenging due to the extracellular and intracellular barriers. In this review, we discuss the utilization of multi-compartmental delivery systems for oral administration of nucleic acid therapies. Some of the illustrative examples of multi-compartmental systems include solid nanoparticles-in-microsphere, solid nanoparticles-in-emulsion, and liquid nanoparticles-in-emulsion. Using type B gelatin nanoparticles encapsulated in poly(ε-caprolactone) microspheres, we have prepared nanoparticles-in-microsphere oral system (NiMOS) for gene and siRNA delivery for the treatment of inflammatory bowel disease (IBD). The results of these studies show that the multi-compartmental formulations can overcome many of the barriers for effective oral gene and siRNA delivery.