Long interspersed element‐1 (LINE1) is the only currently active autonomous retroelement within the human genome. LINE1 replicates itself through a process known as retrotransposition that requires the endonuclease and reverse transcriptase activities of the LINE1 protein ORF2. During retrotransposition, the LINE1 endonuclease recognizes an AT‐rich target sequence loosely defined as 5'TTTT/AA3' (“/” denotes site of cleavage). After nicking of DNA by LINE1 endonuclease and reverse transcription of LINE1 RNA, a new copy of LINE1 is inserted into the genome. The complete details of LINE1 insertion are undefined, however, a double strand break (DSB) must occur during this process prior to integration of novel LINE1 elements. Further studies characterizing LINE1 endonuclease function demonstrated that LINE1 endonuclease induces formation of DSBs. While LINE1 mutagenic insertion events have been associated with diseases such as breast and colon cancer as well as muscular dystrophy, the full effect of LINE1 endonuclease upon stability of the genome is undetermined. Only a small fraction of LINE1‐induced DSBs results in a retrotransposition event suggesting that the damage from the LINE1 endonuclease activity may be greater than previously considered. Thus, an inhibitor of LINE1 endonuclease would be beneficial for estimating LINE1‐associated damage and to potentially minimize LINE1‐related genetic instability. Methodology: We have performed in vitro and in silico screens of small molecule libraries. The small molecules identified will be confirmed for their ability to inhibit the LINE1 endonuclease using in vitro biochemical assays. Results: We have thus far identified a subset of small molecules that inhibit the LINE1 endonuclease. Grant Funding Source: Supported by funding from the Louisiana Cancer Research Consortium and the NIH‐RCMI grant #8G12MD007595‐05 from the National Institute on Minority Health and Health Disparities, and an Institutional Development Award (IDeA) from the National Institut