Zoonotic viruses emerging from wildlife and domesticated animals pose a serious threat to human and animal health and are recognised as the most likely source of the next pandemic. Containment of emerging infectious disease (EID) outbreaks is often difficult due to their unpredictability and the absence of effective control measures, such as vaccines, therapies and diagnostics. RNA interference (RNAi) provides a novel and effective therapeutic strategy to combat infectious diseases through modulation of pathogen and/or host gene expression. In this chapter we discuss the applications of RNAi to combat EIDs. We discuss how RNAi has furthered understanding of virus lifecycles by making possible genome-wide functional genomics studies to discover host functions that are essential for virus replication, and in the process, identify new targets for antiviral therapies. We also discuss the advantages and hurdles associated with the use of RNAi as antiviral therapeutics, in addition to the engineering of disease-resistant livestock using RNAi to protect both humans and animals from EIDs.