The induction of pluripotency in human somatic cells can be achieved by the overexpression of four transcription factors (namely, OCT4, SOX2, KLF4 and MYC). This overexpression can be mediated by retroviral vectors, but there are concerns regarding the safety of this approach. A protein-based approach using purified recombinant proteins, termed cell-permeant proteins (CPPs), or cell extracts containing these proteins has overcome these concerns. But this approach is very inefficient compared with retroviral overexpression. Lee et al. examined target gene expression patterns induced by these two approaches. They found that the virus particles accelerate and augment the expression of the target pluripotency factor genes through Toll-like receptor 3 (TLR3). TLR3 activation caused rapid changes in the expression of epigenetic modifiers to enhance chromatin remodelling and early transcriptional activation. Importantly, the efficacy of CPP-induced pluripotency was greatly enhanced by the inclusion of retrovirus particles or the TLR3 agonist polyI:C.