Induced pluripotent stem cells (iPSCs) share many characteristics with embryonic stem cells, but lack ethical controversy. They provide vast opportunities for disease modeling, pathogenesis understanding, therapeutic drug development, toxicology, organ synthesis, and treatment of degenerative disease. However, this procedure also has many potential challenges, including a slow generation time, low efficiency, partially reprogrammed colonies, as well as somatic coding mutations in the genome. Pioneered by Shinya Yamanaka's team in 2006, iPSCs were first generated by introducing four transcription factors: Oct 4, Sox 2, Klf 4, and c-Myc (OSKM). Of those factors, Klf 4 and c-Myc are oncogenes, which are potentially a tumor risk. Therefore, to avoid problems such as tumorigenesis and low throughput, one of the key strategies has been to use other methods, including members of the same subgroup of transcription factors, activators or inhibitors of signaling pathways, microRNAs, epigenetic modifiers, or even differentiation-associated factors, to functionally replace the reprogramming transcription factors. In this study, we will mainly focus on the advances in the generation of iPSCs with substitutes for OSKM. The identification and combination of novel proteins or chemicals, particularly small molecules, to induce pluripotency will provide useful tools to discover the molecular mechanisms governing reprogramming and ultimately lead to the development of new iPSC-based therapeutics for future clinical applications.