Oral delivery of many therapeutic agents remains challenging due to gastric insolubility/poor dissolution, inefficient intestinal permeability and pre-systemic inactivation. These problems limit the advantages of convenience and increased compliance they provide in the therapy of many chronic diseases. Cyclodextrin nanosystems have emerged as promising platforms for drug-specific construction of the oral delivery nanosystems able to optimize the desired physicochemical properties and pharmacokinetic parameters; without a compromise on safety. This review focuses on some recent and encouraging advances in the application of cyclodextrin nanosystems for oral drug delivery. A general overview of cyclodextrins and pharmaceutical nanotechnology in oral delivery systems is provided. Some of the strategies being exploited for the synthesis of these nanosystems, and their potential for the intelligent navigation of the gastrointestinal tract for optimal bioavailability and biodistribution are then illustrated. Perspectives for translating these nanosystems from laboratory efficient formulations to clinically useful medicines are also discussed.