During development, the genome adopts specific chromatin states to establish and maintain functionally distinct cell types in a well-controlled environment. A select group of transcription factors have the ability to drive the transition of the genome from a pluripotent to a more specialized chromatin state. The same set of factors can be used as reprogramming factors to reset the already established chromatin state back to pluripotency or directly to an alternative cell type. However, under the suboptimal reprogramming conditions, these factors fall short in guiding the majority of cells to their new fate. In this review, we visit the recent findings addressing the manipulation of chromatin structure to enhance the performance of transcription factors in reprogramming. The main emphasis is on the mechanisms underlying the conversion of somatic cells to pluripotency using OSKM. This review is intended to highlight the windows of opportunities for developing mechanistically based approaches to replace the phenotypically guided methods currently employed in reprogramming, in an attempt to move the field of cell conversion towards using next generation technologies.