5'-Phosphorylated nucleoside derivatives are molecules that can be found in all living organisms and viruses. Over the last century, the development of structural analogs that could disrupt the transcription and translation of genetic information culminated in the development of clinically relevant anticancer and antiviral drugs. However, clinically effective broad-spectrum antiviral compounds or treatments are lacking. This viewpoint proposes that molecules that inhibit nucleotide biosynthesis may sensitize virus-infected cells toward direct-acting antiviral nucleosides. Such potentially synergistic combinations might allow the repurposing of drugs, leading to the development of new combination therapies.