Gata4, Gata5, and Gata6 represent a subfamily of zinc-finger transcriptional regulators that are important in the development and differentiation of numerous tissues, including many endodermally-derived organs. We demonstrate that Gata4 and Gata6 have overlapping expression patterns in the early pancreatic epithelium. Later, Gata4 becomes restricted to exocrine tissue and Gata6 becomes restricted to a subset of endocrine cells. In addition, we show Gata6, but not Gata4, physically interacts with Nkx2.2, an essential islet transcription factor. To begin determining the roles that Gata4 and Gata6 play during pancreatic development, we expressed Gata4-Engrailed and Gata6-Engrailed dominant repressor fusion proteins in the pancreatic epithelium and in the islet. At e17.5, transgenic Gata6-Engrailed embryos exhibit two distinct phenotypes: a complete absence of pancreas or a reduction in pancreatic tissue. In the embryos that do form pancreas, there is a significant reduction of all pancreatic cell types, with the few differentiated endocrine cells clustered within, or in close proximity to, enlarged ductal structures. Conversely, the majority of transgenic Gata4-Engrailed embryos do not have a pancreatic phenotype. This study suggests that Gata6 is an important regulator of pancreas specification.