Nucleoside monophosphates and monophosphonates have been known for a long time to exert favorable pharmacological effects upon intracellular delivery. However, their development as drug molecules has been hindered by the inherent poor druglike properties of the monophosphate and monophosphonate groups. These include inefficient cellular uptake and poor in vivo stability, with this latter drawback being most relevant to monophosphates than monophosphonates. To address these limitations, numerous monophosphate and monophosphonate prodrug strategies have been developed and applied in the discovery of nucleoside monophosphate and monophosphonate prodrugs that can treat viral infections and cancer. The approval of sofosbuvir, a nucleoside monophosphate prodrug, highlighted the success to be had by employing these prodrug technologies in the discovery of nucleotide therapeutics. In this Miniperspective, we discuss the different key monophosphate and monophosphonate nucleoside prodrugs that entered clinical development, some of which may in the future be approved to treat various human diseases.