Significant research efforts are underway to generate alternative sources of insulin-producing beta cells for the treatment of diabetes. We have identified Nkx2.2 as a critical regulator of the specification and differentiation of beta cells in mice. Moreover, mutations in human NKX2.2 cause pancreatic defects and neonatal diabetes, demonstrating that the islet functions of Nkx2.2 are conserved between mouse and human. To understand how Nkx2.2 regulates islet cell fate decisions we are exploring the molecular activities of Nkx2.2 in the developing pancreas and in the adult. Importantly, it appears that the functions of Nkx2.2 are intertwined with epigenetic modifications to influence islet cell fate identities. These studies are allowing us to define the complex regulatory activities of Nkx2.2 and epigenetic states that are necessary for specifying and maintaining functional beta cells in the pancreatic islet.