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Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5\u2032-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5\u2032-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5\u2032-monophosphate, which is further transformed to the active 5\u2032-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan\u2019s research to this field is presented. 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