Stem cells are unspecialized cells with the capacity for unlimited self-renewal. Each daughter cell has the capacity to remain a stem cell or to differentiate into more specialized, tissue-specific or organ-specific cells.1 Human embryonic stem cells (hESCs), derived from the inner cell mass of the blastocyst, are pluripotent, which means they can form all lineages of the body (ectoderm, mesoderm, and endoderm). Adult cells can be reprogrammed to an embryonic state using somatic nuclear cell transfer. (This is the technique that was used to create Dolly the sheep.) Adult cells also can be genetically reprogrammed to an embryonic stem cell–like state by being forced to express transcription factors (eg, c -Myc, Sox-2, and Klf4) using retroviruses or lentiviruses.2- 4 Although the therapeutic potential of induced pluripotent stem cells has been demonstrated in animal models of human diseases (eg, sickle cell anemia), these induced pluripotent stem cells have contained multiple viral vector integrations that make them unsuitable for human clinical trials. The use of genome-integrating viruses can cause insertional mutagenesis and unpredictable genetic dysfunction. The oncogenic properties of some transcription factors (eg, c -Myc) also create safety concerns. A number of different strategies are being developed to overcome these obstacles such as development of modified protocols that do not require c -Myc, Sox-2, and/or Klf4 or using expression plasmids rather than integrating viral vectors to deliver the transcription factors. Other strategies to reprogram cells to pluripotency have used modified synthetic messenger RNA or recombinant proteins that can penetrate the plasma membrane of somatic cells or even exposing somatic cells to embryonic stem cell–conditioned media. One or more of these strategies may be safer than using viral vectors to induce reprogramming. Ongoing progress in this area will usher in the era of regenerative medicine.