Engineering RNA viruses to silence the host. Host processing of small RNAs requires sequential enzymatic reactions that begin in the nucleus. For this reason, it was assumed that RNA viruses were incapable of producing miRNAs because the vast majority of these obligate parasites replicate exclusively in the cytoplasm. However, while exploring whether RNA viruses impacted the processing of miRNAs, we discovered that, regardless of the site of replication or the polarity, RNA viruses can be engineered to produce functional miRNAs (Review). Furthermore, as miRNA hairpins can be manipulated at the sequence level, this activity also enables one to make any desired small interfering RNAs (siRNAs) by exploiting the host miRNA machinery (Example). We now use this discovery to generate virus populations with the capacity to individually silence host factors for the purposes of in vivo screening. We have already demonstrated this screening technique can be applied to a diverse collection of viruses. For this research area, pooled libraries of viruses, identical at the protein level but uniquely encoding a single siRNA capable of silencing a defined host factor, are used to perform high throughput screening in vivo. These virus libraries can be applied to a variety of pressures to allow natural selection to parse out host factors that inhibit replication and/or restrict tropism.