During the reporting period, we have made significant progress toward the following research aims: (1) Using the reprogramming assay system established in year one, we continue to screen and identify small molecules that can replace reprogramming transcription factors to generate induced pluripotent stem (iPS) cells from human somatic cells. Based on our earlier success on reprogramming neonatal human keratinocytes and endothelial cells into iPS cells using a single transcription factor, Oct4, and a combination of small molecules, we further optimize the conditions that allowed us to reprogram clinically more relevant and practical adult human keratinocytes and also mesenchyml/fibroblastic cells (isolated from amnion fluid) into full iPS cells. (2) Using standard assays, we have characterized those iPS cells to be pluripotent in vitro and in vivo. (3) Most importantly, we characterized a new fundamental mechanism of reprogramming involving a metabolic switch. Such new mechanistic insight has since provided new guidance and strategies to optimize the reprogramming conditions.