Despite advances in drug-delivery technologies, successful oral administration of protein drugs remains an elusive challenge. When protein drugs are administered orally, they can rapidly denature or degrade before they reach their targets. Such drugs also may not absorb adequately within the small intestine. As a protein drug for treating diabetes, insulin is conventionally administered via subcutaneous (SC) injection, yet often fails to achieve the glucose homeostasis observed in nondiabetic subjects. Some of this difference may relate to insulin transport: normally, endogenously secreted insulin moves to the liver via portal circulation. When administered subcutaneously, insulin moves through the body via peripheral circulation, which can produce a peripheral hyperinsulinemia. In addition, because SC treatment requires multiple daily injections of insulin, patients often do not fully comply with treatment. Oral administration of exogenous insulin would deliver the drug directly into the liver through portal circulation, mimicking the physiological fate of endogenously secreted insulin. This characteristic may offer the needed hepatic activation, while avoiding hyperinsulinemia and its associated long-term complications. This Account demonstrates the feasibility of using chitosan nanoparticles for oral insulin delivery. Nanoparticle (NP) delivery systems may provide an alternative means of orally administering protein drugs. In addition to protecting the drugs against a harmful gastric environment, the encapsulation of protein drugs in particulate carriers can avert enzymatic degradation, while controlling the drug release and enhancing their absorption in the small intestine. Our recent study described a pH-responsive NP system composed of chitosan (CS) and poly(γ-glutamic acid) for oral delivery of insulin. As a nontoxic, soft-tissue compatible, cationic polysaccharide, CS also adheres to the mucosal surface and transiently opens the tight junctions (TJs) between contiguous epithelial cells. Therefore, drugs made with CS NPs would have delivery advantages over traditional tablet or powder formulations. This Account focuses on the premise that these CS NPs can adhere to and infiltrate the mucus layer in the small intestine. Subsequently, the infiltrated CS NPs transiently open the TJs between epithelial cells. Because they are pH-sensitive, the nanoparticles become less stable and disintegrate, releasing the loaded insulin. The insulin then permeates through the opened paracellular pathway and moves into the systemic circulation.