MicroRNAs (miRNAs) are small regulatory RNAs that play a defining role in post-transcriptional gene silencing of eukaryotes by either mRNA cleavage or translational inhibition. Plant miRNAs have been implicated in innumerable growth and developmental processes that extend beyond their ability to respond to biotic and abiotic stresses. Active in an organism's immune defence response, host miRNAs display a propensity to target viral genomes. During viral invasion, these virus-targeting miRNAs can be identified by their altered expression. All the while, pathogenic viruses, as a result of their long-term interaction with plants, have been evolving viral suppressors of RNA silencing (VSRs), as well as viral-encoded miRNAs as a counter-defence strategy. However, the gene silencing attribute of miRNAs has been ingeniously manipulated to down-regulate the expression of any gene of interest, including VSRs, in artificial miRNA (amiRNA)-based transgenics. Since we currently have a better understanding of the intricacies of miRNA-mediated gene regulation in plant-virus interactions, the majority of miRNAs manipulated to confer antiviral resistance to date are in plants. This review will share the insights gained from the studies of plant-virus combat and from the endeavour to manipulate miRNAs, including prospective challenges in the context of the evolutionary dynamics of the viral genome. Next generation sequencing technologies and bioinformatics analysis will further delineate the molecular details of host-virus interactions. The need for appropriate environmental risk assessment principles specific to amiRNA-based virus resistance is also discussed.