Summary Endogenous retroviruses and related transposable elements make up much of our genome, and active forms persist as long interspersed element-1 (LINE-1, L1) retrotransposons and the elements it mobilizes. These are self-propagating sequences which copy themselves through the reverse transcription of RNA intermediates. We have developed elaborate mechanisms to silence their transcription and limit their proliferation. However, a careful approach to RNAseq analysis reveals that that a subset of individual transposon loci (ITL) escape silencing and are transcriptionally active. In a survey of normal human cells, we identify both constitutive and variably expressed ITL. Our ability to measure these transcripts provides a unique opportunity to examine this host-pathogen relationship and its role in gene regulation. Here, we propose to test the hypothesis that retroelement expression (or lack thereof) is an indicator of specific regulatory mechanisms with cis-acting effects on neighboring genes. We propose to define the landscape of expressed retrotransposons in humans; demonstrate molecular mechanisms of transcriptional silencing and escape; and probe how these mechanisms affect gene expression in human ‘epigenetic’ diseases. We will use genome editing strategies to test whether altering ITL sequences affects neighboring gene expression. Finally, we will develop approaches to study prevalent, highly-expressed short interspersed elements (SINEs) to assess their potential for retrotransposition, determine whether they are targets of RNA editing or dsRNA sensing pathways, and test their interactions with cellular mRNAs in trans. These studies will be among the first to delve into the expression and function of a broad range of retrotransposon intermediates in human cells.