In this issue of the Journal of Medicinal Chemistry, Janeba et al. found that the in vitro antiviral activity and selectivity index of the aryloxy phosphoramidate (ProTide) prodrug of the acyclic nucleoside phosphonate tenofovir (tenofovir alafenamide) can be dramatically improved by replacing the aryloxy pro-moiety with an appropriate tyrosine derivative. This Viewpoint highlights the possible impact and ramifications that these findings may have in the development of new ProTides.