There has been a paradigm shift in our understanding of how protein regulation occurs within mammalian cells in the last 15 years. Our current understanding is that small, noncoding RNA molecules called microRNAs (miRNAs) play a vital role in modulating the translation of mRNAs into protein. Important studies suggest that HIV-1 replication may be restricted by certain host cellular miRNAs, and this in turn may play pivotal roles in host defense and in maintaining latency within resting CD4 T cells. Conversely, host cellular miRNAs have also been demonstrated to be essential for certain viruses to establish infection and the altered expression of cellular miRNAs in the setting of HIV-1 may also be a factor favoring viral replication. The differential expression of important protective histocompatability locus antigen (HLA) alleles in HIV-1 infection has recently been shown to be regulated by miRNAs. To date, most efforts into finding an effective vaccine to combat HIV-1 have not been successful. Understanding the role that miRNAs may play in HIV-1 pathogenesis may allow a different approach to targeting key small RNAs or the identification of new important protein targets regulated by miRNAs, which may result in a better vaccine construct. The purpose of this review is to look at our current state of understanding of how HIV-1 and the miRNA pathway interact and the possible therapeutic interventions that this knowledge may entail.