Nearly 50 years have passed since the concept of nuclear reprogramming was proposed for the first time. Since then, several approaches have been developed to convert somatic cells to a pluripotent state. Direct reprogramming with defined factors, is the newest of these approaches. This method requires just a few genes, and it also has a great reproducibility. Applying this method to humans seems to open the door to cell transplantation therapy without immune rejection, drug discovery, and elucidation of the pathogenesis of intractable diseases. However, this concept still faces some issues which must be overcome before application due to a shortage of experience. This chapter introduces an overview of direct reprogramming as well as a special focus on its potentials and challenges.