RNAi plays important roles in many biological processes, including cellular defense against viral infection. Components of the RNAi machinery are widely conserved in plants and animals. In mammals, microRNAs (miRNAs) represent an abundant class of cell encoded small noncoding RNAs that participate in RNAi-mediated gene silencing. Here, findings that HIV-1 replication in cells can be regulated by miRNAs and that HIV-1 infection of cells can alter cellular miRNA expression are reviewed. Lessons learned from and questions outstanding about the complex interactions between HIV-1 and cellular miRNAs are discussed.