Reprogramming somatic cellsto become induced pluripotent stem cells(iPSCs) byusing defined factorsrepresents an important breakthrough in biology and medicine, yet remains inefficient and poorly understood. We therefore devised synthetic factors byfusing the VP16 transactivation domain to OCT4 (also known as Pou5f1), NANOG and SOX2, respectively. These synthetic factorscould reprogramme both mouseand humanfibroblasts with enhanced efficiency and accelerated kinetics. Remarkably, Oct4-VP16 alone could efficiently reprogramme mouseembryonic fibroblasts (MEFs) into germline-competent iPSCs. Furthermore, episomally delivered synthetic factorscould reproducibly generate integration-free iPSCs from MEFs with enhanced efficiency. Our results not only demonstrate the feasibility ofengineering more potent reprogramming factors, but also suggest that transcriptional reactivation ofOCT4 target genes might be a rate-limiting step in the conversion of somatic cellsto pluripotent cells. Synthetic factor-based reprogrammingmight lead to a paradigm shift in reprogrammingresearch.