Human embryonic stem (hES) cells and induced pluripotent (iPS) cells hold great promise as regenerative therapies for a number of currently incurable human diseases. However, before these cells or their progeny can be used as infusion therapies, the safety of these cells must be confirmed. One important safety concern is that during the generation, expansion, and manipulation of these pluripotent cells, mutations may be introduced into their genomes as a result of the activation and “jumping” of endogenous mobile genetic elements. Human cells contain roughly 3 million endogenous retroelements that comprise slightly less than half of the DNA present in the entire genome. Although many of these retroelements have been permanently silenced due to mutations, many others remain retrotransposition-competent and are capable of producing RNA, converting this RNA back into DNA (reverse transcription) and inserting this DNA at new sites in the cellular genome. These new insertions expand the cell’s pool of DNA and potentially produce disease-causing mutations or cancer. In somatic cells, the expression of these retroelements is strongly repressed through DNA methylation. However, because of the dynamic changes in DNA methylation that occur during the generation of iPS cells, high level retroelement retrotransposition may be unleashed. Our CIRM-sponsored work focuses on assessing endogenous retroelement activity as skin cells are reprogrammed into iPS cells. In the last 6 months, we have demonstrated that endogenous retroelements jump during iPS cell reprogramming and that the iPS cells generated contain new retroelement insertions in their genomes. We are now creating a new method to monitor the retroelement retrotransposition more accurately during reprogramming. In addition we are exploring both small molecules and cellular defenses that may counter retroelement retrotransposition in iPS cells (e.g., DNA methylation, APOBECs, TREX-1, and the RNAi machinery). Together, our goal is to provide a safer way to produce, culture and expand pluripotent cells.