The therapeutic potential of embryonic stem cells (ESc) is a key scientific interest, but the ethical implications of stem cell research have been controversial and are often a major detriment to the advancement of our knowledge. Recently, several landmark studies both in mouse and human have defined a set of four transcription factors (Klf4, c-Myc, Oct4 and Sox2) whose ectopic expression enables a somatic nucleus to shift back to a pluripotent state. These cells, referred to as induced pluripotent stem (iPS) cells, not only express markers characteristic of pluripotent cells such as alkaline phosphatase, SSEA1, Nanog and Oct4, but both their epigenetic state and their biological potency have been shown to be indistinguishable from those of ES cells. Although these results have been a great breakthrough in stem cell research and have brought hope for an alternative to embryo-derived ES cells, skeptics argue that these pluripotent cells derive from a small subset of remaining multipotent cells or cells that are more amenable to direct reprogramming. Following this approach, a fundamental question remains unsolved: namely, whether this process holds true in terminally differentiated cells. Also, clarifying whether cells of a distinct lineage are equally amenable to direct reprogramming throughout their developmental stages would determine if distinct prerequisites are needed and would be an important step towards understanding the biological processes involved in this transformation. Here, we used transgenic and inducible expression vectors of the previously described factors to reprogram mouse B lymphocytes. Alone, the four factors were able to convert non-terminally differentiated pro-B cells into a pluripotent state but failed to do so in cells that had undergone full B cell receptor rearrangements. Instead, expression of a myeloid transcription factor CCAAT/enhancer-binding-protein-α (C/EBPα), known to disrupt the epigenetic faith of B cells, was shown to be required. Multiple iPS lines were derived and characterized using various methods. Ultimately, they were shown to be fully pluripotent by their contribution to germline transmission. Our study provides definitive proof for the direct nuclear reprogramming of terminally differentiated adult cells to pluripotency