RNA interference (RNAi) mediated virus resistance was first discovered by Waterhouse et al. [69] against the Potato virus Y in transgenic tobacco plants. RNA mediated gene control mechanism has provided a new platform for developing molecular tools for gene functions study and crop improvements [70]. RNA silencing pathways play a role in both biotic and abiotic stress responses in plants defence against pathogens and insects that will help humankind to face the challenges of productive agriculture in the increasingly unfavourable environmental conditions associated with climate change. This technology can be used for generating disease resistance by suppressing a specific gene or genes [71]. PRSV is an RNA virus containing a single open reading frame translated into a large polyprotein that produced the final protein products [72]. RNA-mediated protection would be effective only when the transgene is highly similar to the attacking virus. The differences between geographically distinct isolates have made the creation of PRSV-resistant transgenic plants difficult. The failure of PRSV resistance has frequently involved the silencing by suppressor proteins of viral origin [73]. This problem can be overcome by the silencing suppressor protein HcPro, through an RNA-silencing mechanism within transgenic papaya. The helper component proteinase (HcPro) has been shown to be a highly effective suppressor of RNA silencing. Mangrauthia et al. [74] suggested that HcPro is an important component which needs to be taken into consideration for the development of PRSV-resistant papaya on the Indian subcontinent. The mechanism of RNA-mediated virus resistance is also referred to as homology dependency resistance to reflect the specific mechanism of posttranscriptional gene silencing (PTGS) [75, 76]. PTGS is the accumulation of 21–25 nucleotide small-interfering RNAs, the sequence-specific degradation of target mRNAs, and the subsequent methylation of target gene sequences. Tennant et al. [77] reported that mechanisms of transgenic papaya resistance against PRSV are sequence homology dependent and mediated by RNA via PTGS. They found that an untranslatable CP gene was able to confer resistance to the homologous strain of the virus isolate of PRSV by PTGS. On the other hand, the silencing suppressor was the main factor for the suppression of PRSV transgenic resistance [78]. Ruanjan et al. [73] reported that transgenic papaya showed resistant to PRSV by suppressing posttranscriptional gene silencing (PTGS).