A milestone recently achieved by Yamanaka and Takahashi was the conversion somatic cells into induced pluripotent stem cells (iPSCs) by over-expressing combinations of defined transcription factors, Oct4, Sox2, Klf4, and c-Myc (OSKM). Despite the great potential for regenerative medicine, iPSC technology provides a remarkable model to study the intrinsic molecular and epigenetic mechanism of this cell fate transition. However, induction of iPSCs by the four transcription factors is an inefficient and lengthy process. One of the challenging tasks for the reprogramming factors is to reset the epigenetic status, which is regulated by the chromatin structure and its epigenetic modifications such as DNA methylation and histone modifications. Here, we explore the function of two epigenetic co-regulators, nuclear receptor co-repressor (NCoR) and silencing mediator for retinoid and thyroid hormone receptor (SMRT or NCoR2), in modulating the transcriptional output during somatic cell reprogramming. NCoR and SMRT are two co-repressors, which have recently shown to have important function in cell fate determination, cell differentiation, and lineage progression. However, the role of NCoR and SMRT in somatic cell reprogramming is not been reported. Interestingly, abolishing the repressive effect of NCoR and SMRT greatly enhance the iPSC efficiency and kinetics. Moreover, reprogramming factors themselves, especially c-Myc, have the ability to recruit NCoR and SMRT to their target pluripotency genes and therefore, subsequently constitutes an epigenetic block to reprogramming. We also demonstrate that these repressive effects are dependent on Hdac3, which executes the repressive function of NCoR and SMRT complex in reprogramming by inducing histone deacetylation. Furthermore, even dispensable for maintaining the pluripotent state of embryonic stem cells (ESCs), NCoR but not SMRT seem to regulate several master regulators of the primitive endoderm. Taken together, we uncover that reprogramming specific engagement of co-repressor complex NCoR and SMRT constitutes an epigenetic barrier in somatic cell reprogramming.