The WW domain is a modular protein structure that recognizes the proline-rich Pro–Pro-x-Tyr (PPxY) motif contained in specific target proteins. The compact modular nature of the WW domain makes it ideal for mediating interactions between proteins in complex networks and signaling pathways of the cell (e.g. the Hippo pathway). As a result, WW domains play key roles in a plethora of both normal and disease processes. Intriguingly, RNA and DNA viruses have evolved strategies to hijack cellular WW domain–containing proteins and thereby exploit the modular functions of these host proteins for various steps of the virus lifecycle, including entry, replication, and egress. In this review, we summarize key findings in this rapidly expanding field, in which new virus–host interactions continue to be identified. Further unraveling of the molecular aspects of these crucial virus–host interactions will continue to enhance our fundamental understanding of the biology and pathogenesis of these viruses. We anticipate that additional insights into these interactions will help support strategies to develop a new class of small-molecule inhibitors of viral PPxY–host WW domain interactions that could be used as antiviral therapeutics.