In this review, a quick presentation of what interfering RNA (iRNA) are--small RNA able to exert an inhibition on gene expression at a posttranscriptional level, based on sequence homology between the iRNA and the mRNA--will be given. The many faces of the interrelations between iRNA and viruses, particularly HIV, will be reviewed. Four kinds of interactions have been described: i) iRNA of viral origin blocking viral RNA, ii) iRNA of viral origin downregulating cellular mRNA, iii) iRNA of cellular origin (microRNA) targeting viral RNA, and iv) microRNA downregulating cellular mRNA encoding cell proteins used by the virus for its replication. Next, HIV strategies to manipulate these interrelations will be considered: suppression of iRNA biosynthesis by Tat, trapping by the HIV TAR sequence of a cell component, TRBP, necessary for iRNA production and action, and induction by the virus of some microRNA together with suppression of others. Then, we will discuss the putative effects of these mutual influences on viral replication as well as on viral latency, immune response, and viral cytopathogenicity. Finally, the potential consequences on the human infection of genetic polymorphisms in microRNA genes and the therapeutic potential of iRNA will be presented.