During the reporting period, we have made significant progress toward discovering new molecules that can enhance reprogramming of human somatic cells to become pluripotent stem cells with minimal genetic manipulation. Specifically, using the reprogramming assay system established, we continued to screen and identify new small molecules that can enhance reprogramming efficiency under a single reprogramming factor/Oct4 condition to generate induced pluripotent stem (iPS) cells from human somatic cells. Using standard assays, we have characterized those iPS cells to be pluripotent in vitro and in vivo. Most importantly, we characterized another new fundamental mechanism of reprogramming involving mitochondrial metabolism. Such new mechanistic insight has since provided new guidance and strategies to optimize the reprogramming conditions.