Abstract Regenerative medicine has received much attention over the years due to its clinical and commercial potential. The excitement around regenerative medicine waxes and wanes as new discoveries add to its foundation but are not immediately clinically applicable. The recent discovery of induced pluripotent stem cells has lead to a sustained effort from many research groups to develop clinically relevant regenerative medicine therapies. A major focus of cellular reprogramming is to generate safe cellular products through the use of proteins or small molecules instead of transgenes. The successful reprogramming of somatic nuclei to generate pluripotential cells capable of embryo development was pioneered over 50 years ago by Briggs and King and followed by Gurdon in the early 1960s. The success of these studies, the cloning of Dolly, and more current studies involving adult stem cells and transdifferentiation provide us with a large repository of potential candidate molecules and experimental systems that will assist in the generation of safe, transgene-free pluripotential cells.