The ability to reprogram somatic cells into induced pluripotent stem cells (iPSCs), which can differentiate into all embryonic lineages, has become a cornerstone of regenerative medicine. Reprogramming is induced by overexpressing a select set of transcription factors, but this method is somewhat inefficient. To find novel factors involved in somatic cell reprogramming, Vincent Pasque and colleagues (Vanheer et al., 2019) now use an siRNA candidate screen in mouse embryonic fibroblasts undergoing reprogramming and identify Tox4 as a mediator of cell fate reprogramming. The authors show that the formation of early and intermediate reprogramming intermediates is reduced upon Tox4 knockdown. They further indicate two potential mechanisms by which Tox4 aids the early stages of reprogramming: firstly, Tox4 is needed to extinguish the expression of selected somatic genes upon induction of reprogramming and, secondly, it promotes the expression of the OKSM reprogramming factors. Tox4 appears to influence gene expression by regulating the chromatin landscape; Tox4 knockdown promotes open chromatin at a subset of chromosomal regions typically accessible to transcription factors in somatic cells, whereas pluripotency-related chromosomal regions are less accessible upon Tox4 knockdown. Together, these findings characterise Tox4 as a novel regulator of the early stages of somatic cell reprogramming and contribute to our understanding of the pathways governing reprogramming to iPSCs.