Since the discovery of miRNAs, a class of endogenous non-coding cellular RNAs of 18-25 nucleotides that binds to a complementary sequence in the 3′ UTR of target mRNAs to regulate target gene expression mostly at the post-transcriptional level, their potential application for the treatment of infectious diseases is being investigated (Ghosh et al. 2009). In this context, some miRNAs are involved in the host antiviral response, acting as factors with antiviral activity. For example, the miRNA let-7b inhibits Hepatitis C Virus (HCV) RNA expression and replication by targeting the host factor insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) (Cheng et al. 2013). The 3′ end of the Human immunodeficiency virus type 1 (HIV-1) mRNA is also reported to be a target for a group of miRNAs expressed in resting CD4+ T cells (miR-28, -125b, -150, -223, and -382) that may inhibit translation and cause a latent infection in these cells (Huang et al. 2007). Recently, six single miRNAs targeting the highly conserved regions of the DENV-2 genome were shown to efficiently inhibit virus replication (Xie et al. 2013). However, DENV infection significantly induced the expression of miR-146a, thereby facilitating viral replication by targeting tumour necrosis factor receptor-associated factor 6 (TRAF6) and diminishing interferon-β (IFN-β) production (Wu et al. 2013). Additionally, incorporation of miR-122-MRE (miRNA recognition element) confers an inhibitory susceptibility to miR-122 targeting the DENV replicon, suggesting that DENV can be engineered to exert the desired replication restriction effect for avoiding infection of vital tissues/organs (Lee et al. 2010). Recently it was reported that DENV infection up-regulates the expression of miR-30e* but overexpression of this miRNA simultaneously suppresses DENV replication by promoting IFN-β production (Zhu et al. 2014). Overexpression of miR-548g-3p suppresses the replication of all four DENV serotypes (Wen et al. 2015) and we have demonstrated that overexpression of synthetic miR-133a suppresses DENV-2 replication, possibly through regulating the expression of PTB, a miRNA-133a target, since its protein was found to be upregulated during DENV infection (Castillo et al. 2016). Furthermore, we found that the 3′ UTR of the RNA of all four DENV serotypes is targeted by miR-133a. However, members of the Flavivirus genus were recently reported to produce a subgenomic flavivirus RNA (sfRNA), a positive-sense non-coding RNA that accumulates to high levels in infected mammalian and insect cells (Lin et al. 2004). Interestingly, this sfRNA acts as an RNA interference (RNAi) suppressor in both insect and mammalian cells, inhibiting the RNase Dicer (Schnettler et al. 2012). This is why the discovery of cellular miRNAs recognising target sequences in the DENV genome would be vital, possibly leading to a treatment for dengue, for which there is no vaccine or therapeutic drug yet.