Virus transmission by aphids involves a combination of biological players that have co-evolved over years of interaction: plant hosts, aphid vectors, plant viruses and the aphid’s bacterial endosymbiont. In this interaction, plant hosts activate their immune defenses against plant viruses and aphids and the latter two use a myriad of strategies to overcome, counteract or skip the host plant defense, which sometimes is done in collaboration. Bacterial endosymbionts of insect vectors might also play a role in virus transmission, either directly or indirectly, as I discussed in a critical literature review. I used proteomics and aphid genetics to show that the “biotype” phenotype of aphids is generated by genetic recombination in sexual reproduction and that aphid virulence and virus transmission are independent traits. I also showed that the host plant where aphids are reared on affects the aphid ability to transmit a circulative virus, the Luteovirid Potato leafroll virus (PLRV). Using organismal, biochemical, molecular, and imaging approaches, I show that the differential expression and activity of gut cysteine proteases at the cell membrane of aphids reared on a PLRV non-host plant is responsible for the change in virus transmission phenotype. Finally, using small RNA sequencing, I showed that aphids do not activate their small interference RNA (siRNA) antiviral defense against PLRV, which provides additional evidence for the lack of replication of Luteovirids in their aphid vectors. However, aphids produce 22 nt long siRNA as an immune defense against an aphid virus, Myzus persicae Densovirus (MpDNV), which infects and replicates in the aphid. Strikingly, an abundance of unusually large sRNA, from 33 to 38 nt that aligned to MpDNV were produced only in aphids fed on PLRV-infected plants, suggesting that feeding on a plant infected with a circulative virus modulates the aphid antiviral immune defenses. The function of these large sRNAs is not yet known.