Developing cell-based diabetes therapies requires examining transcriptional mechanisms underlying human β cell development. However, increased knowledge is hampered by low availability of fetal pancreatic tissue and gene targeting strategies. Rodent models have elucidated transcription factor roles during islet organogenesis and maturation, but differences between mouse and human islets have been identified. The past 5 years have seen strides toward generating human β cell lines, the examination of human transcription factor expression, and studies utilizing induced pluripotent stem cells (iPS cells) and human embryonic stem (hES) cells to generate β-like cells. Nevertheless, much remains to be resolved. We present current knowledge of developing human β cell transcription factor expression, as compared to rodents. We also discuss recent studies employing transcription factor or epigenetic modulation to generate β cells. © 2014 Elsevier Ltd.