We have developed a new method for iPS cell induction to increase the safety by using novel factor Glis1. We screened more than 1,400 human transcription factors for the ability to replace Klf4 and discovered a novel transcription factor Glis1. Glis1 has the synergistic effect of Glis1 and Yamanaka 3 factors (Oct3/4, Sox2, Klf4) for iPS cell induction. Moreover this factor, enriched in unfertilized and recently fertilized eggs, could replace c-Myc to produce iPS cells from somatic cells with higher efficiency and decreased tumorigenicity. Glis1 promotes iPS cell generation effectively and specifically by activating multiple pro-reprogramming pathways. Glis1 also suppresses the proliferation of defective partially reprogrammed cells. We conclude that the improved safety and efficiency of iPS cell production using Glis1 would be beneficial for future applications of iPS cell technology.