Building on the discovery that MyoD expression reprograms fibroblasts into muscle, three papers (Vierbuchen et al., 2010, Ieda et al., 2010, Szabo et al., 2010) recently reported the reprogramming of fibroblasts into neurons, cardiomyocytes, and blood cell progenitors without first passing the cells through a pluripotent state. Here we discuss the advantages and challenges of harnessing this direct reprogramming method for regenerative medicine.