Traditionally, antiviral drugs target viral enzymes and or structural proteins, identified through large drug screens or rational drug design. The screening, chemical optimisation, small animal toxicity studies and clinical trials mean time to market is long for a new compound, and in the event of a novel virus or pandemic, weeks, and months matter. Small interfering RNAs (siRNAs) as a gene silencing platform is an alluring alternative. SiRNAs are now approved for use in the clinic to treat a range of diseases, are cost effective, scalable, and can be easily programmed to target any viral target in a matter of days. Despite the large number of preclinical studies that clearly show siRNAs are highly effective antivirals this has not translated into clinical success with no products on the market. This review provides a comprehensive overview of both the clinical and preclinical work in this area and outlines the challenges the field faces going forward that need to be addressed in order to see siRNA antivirals become a clinical reality.