Significance Reprogramming of somatic cells holds tremendous therapeutic promise. Here we show that a key barrier to this process is a DNA binding protein named activator protein 1 (AP-1). We find that AP-1 acts sequentially to first maintain the somatic state by turning genes on and then to block the initiation of the new cellular program by acting as a repressor of gene transcription. Crucially, we were able to uncover this feature of AP-1 by using the heterokaryon system of reprogramming, in which human fibroblasts are fused to an excess of mouse embryonic stem cells to favor the induction of the embryonic stem cell program in the fibroblast.