Human pancreatic beta cells are lost or reduced in numbers in both Type 1 and Type 2 diabetes. This has prompted attempts to induce human beta cells to regenerate, or to replace beta cells from cadaveric donors. In the US, there are 26 million people with diabetes, but only ~2000 pancreas organ donors per year, so that replacement of beta cells from cadaveric sources is not feasible on a large scale. Thus, there is an urgent need to induce human beta cells to replicate or regenerate in vivo in people with diabetes as well as ex vivo to generate sufficient supplies of human beta cells for beta cell replacement therapy. With these thoughts in mind, we have attempted to develop approaches to inducing human beta cells to proliferate and expand. Unfortunately, this has proven difficult, because human beta cells have proven resistant to mitogens, growth factors, small molecules and biologics that induce rodent beta cells to replicate. Accordingly, we have explored the molecular control at the G1/S checkpoint of human beta cell cycle control, and have shown that human beta cells are amenable to induction of cell cycle entry through manipulation of cyclins and cdks. Moreover, cyclin- and cdk-mediated cell cycle induction leads to enhanced function in human islets transplanted into immunodeficient diabetic rodent models. Our efforts at expanding human beta cells has now extended to manipulation of upstream signaling pathways and high-throughput small molecule screens, both of which have yielded promising approaches to therapeutic human beta cell expansion. These will be discussed in the meeting.