RNA interference (RNAi) is an evolutionarily conserved gene-silencing mechanism in which small 19–23-nucleotide double-stranded RNA molecules, or small interfering RNAs (siRNAs), target cognate RNA for destruction with exquisite potency and selectivity. The RNAi machinery is believed to be expressed in all eukaryotic cells and has been shown to regulate host gene expression. Given this ability, RNAi silencing strategies have been developed to inhibit viral genes and replication in host cells. One area of growing interest is the development of synthetic siRNA drugs to target acute viral infections in which long-term gene silencing is not required or desirable. To achieve synthetic siRNA drug efficacy, these anti-viral agents need to be delivered to the appropriate host cells, as they do not readily cross the cell membrane. Varied delivery and siRNA chemical stabilization strategies are being investigated for siRNA drug delivery; however, several studies have shown that naked, unmodified siRNA drugs can be effective in silencing replication of some viruses in animal models of infection. These findings suggest that RNAi-based drugs may offer breakthrough technology to protect and treat humans and animals from viral infection. However, there are four major considerations for evaluating successful RNAi efficacy: the siRNAs must have high efficiency, show low cytotoxicity, result in minimal off-target effects, and lead to results that are reproducible between experiments. The methods and caveats to achieve these goals are discussed.