The process of pancreatic islet cell development, differentiation and maturation is coordinately regulated by many conserved and well-characterized transcription factors. Interestingly, many of these factors physically interact with Groucho (Grg/TLE) co-repressor proteins. Grg proteins do not bind directly to DNA, but interact with site-specific DNA binding factors to convert them to transcriptional repressors. We have determined that several members of the Grg family are expressed during pancreas development and in the adult islet where they modulate cell-specific and promoter-specific transcription factor activities. We are using mutational analysis to identify the functions of Grg proteins in regulating islet cell-specific gene expression and islet cell development. These studies are allowing us to define the complex transcriptional regulatory networks that are necessary for specifying and maintaining functional beta cells in the pancreatic islet.