Ever since the derivation of the first human embryonic stem cell line, hopes have persisted for the treatment of a wide range of cellular degenerative diseases. However, significant immuno-incompatibility between donor cells and recipient patients remains an unsolved challenge. Currently, three main strategies are investigated in humans to create autologous pluripotent stem cells: somatic cell nuclear transfer, cell fusion and cell extract incubation. All methods exploit the fact that a somatic genome is amenable to epigenetic dedifferentiation into a more plastic state, presumably through direct exposure to and manipulation by heterologous transcriptional factors. Epigenetic reprogramming includes profound modifications of chromatin structure, but the responsible mechanisms that work in toti- and pluripotent cells remain largely unknown. This review presents a brief introduction to stem cell terminology and epigenetics, followed by a critical examination of the predominant methodologies involved. Finally, the search for specific reprogramming factors is discussed, and obstacles for the clinical implementation of reprogrammed cells are addressed.