Safeguarding the genome is essential for cells’ proper functions, and more importantly for safe and efficacious applications involving pluripotent stem cells and adult stem cells. However, how pluripotent or somatic stem cells maintain genome integrity during self-renewal, differentiation, and reprogramming is still largely unknown. In the past year, we continue to characterize a novel small molecule that was previously identified and shown to protect and enhance repairing of stem cell genome under genotoxic stress conditions. We found that the small molecule can accelerate DNA damage repair in several human cell types. Furthermore, we have designed and synthesized its new analogs and identified its structure-activity-relationship. Moreover, we attempted affinity pull-down for target identification and began to test several target candidates. A better understanding of mechanisms involved in regulating genome stability and DNA repair in stem cells, and more importantly developing new and practically useful approaches (e.g., small molecules) to improve genome maintenance and damage repair would be highly desirable.