Retroelements (including transposons, retrotransposons, retroviruses, and lentiviruses) make up a significant portion of eukaryotic genomes. Given their ability to mutate genes these mobile elements always present a threat to the integrity of the host genomes. Recent studies have revealed complex molecular mechanisms that silence the mutagenic ability of these RE as well strategically express the pieces of the incorporated RE that are utilized to silence human endogenous retroviruses (HERVs) or invading exogenous retroviruses (IERV). We have hypothesized that small endogenous RNA originally evolved to quell 'foreign" IERV-genes and subsequently emerged into elaborate silencing systems that include RNA interference, miRNA-based gene regulation and other gene silencing mechanisms. Here, we present evidence that the replication of complex RE are most likely silenced or regulated by homologous miRNA that are found as a part of the cellular repertoire. We analyzed Homo sapiens miRNAs for possible target genetic sequences in selected HERVs and IERV found in humans and other large primates. We identified several miRNAs that have >80% sequence homology with human HERVs; -L, -W, and -K, and IERV like SIVcpz, HTLV-1, and HTLV-2. We found an inverse correlation between the numbers and relative degree of homology of miRNAs to the relative replication capacity of a specific RE. Therefore, larger numbers of miRNAs with greater degree of homology are found against the least active RE and the least numbers of miRNAs with smaller degree of homology are found against the most active RE (i.e. HERV-K). Implications of these observations in RE disease and therapy are discussed. (c) 2008 Elsevier Inc. All rights reserved.