MicroRNAs are recently discovered small endogenous non-coding RNAs. These small RNAs of approximately 22 nucleotide length are crucial post-transcriptional regulators of gene expression in a wide spectrum of normal and abnormal biological processes including antiviral defence, oncogenesis and development in higher eukaryotes. Of late, a number of viruses have also been shown to encode for microRNAs. The host- and virus-encoded microRNAs and their targets together thus form a novel regulatory layer of genetic interactions between the host and the virus. Recent reports have thrown light on this new regulatory layer. A clear understanding of the cross-talk between the host and virus would not only enable us to understand the molecular basis of viral pathogenesis, but also enable us to develop better therapeutic strategies. This review discusses the intricacies of host-virus cross-talk mediated by microRNAs. Recent trends in this field and the challenges that need to be addressed are also discussed.