It is becoming clear that viruses interface with the mRNA decay machinery in a variety of ways during an infection. First, RNA viruses in particular must evade the mRNA decay machinery long enough to replicate and establish infection. Second, many viruses usurp or augment cellular mRNA decay pathways to regulate or selectively express their own genes, often inducing massive decay of the host transcripttome. Finally, temporal progression of a viral infection can depend on regulated decay of specific viral transcripts. Therefore, in order to fully understand viral biology, we must take into account the interactions between viruses and the mRNA decay machinery. This approach gives insights into regulatory mechanisms of cellular mRNA decay, as well as reveals novel ways to influence the outcome of viral infections.