The reprogramming of somatic cells into induced pluripotent stem cells or iPS cells can be achieved by the ectopic expression of defined factors. Patient-specific iPS cell lines can be derived and used for disease modeling, drug and toxicology screening, cellular replacement therapies and basic research. However, reprogramming is slow and inefficient and numerous methods have been described aiming to improve this process. These methods include screening for new genetic factors and chemical compounds, and the engineering of new synthetic factors. Here, we review recent progress made in this field and show how a better understanding of the ES (embryonic stem) cell transcriptional network is important for efficient reprogramming.