The dual nature of pancreatic tissue permits both endocrine and exocrine functions. Enzymatic secretions by the exocrine pancreas help digestive processes while the pancreatic hormones regulate glucose homeostasis and energy metabolism. Pancreas organogenesis is defined by a conserved array of signaling pathways that act on common gut progenitors to bring about the generation of diverse cell types. Multiple cellular processes characterize development of the mature organ. These processes are mediated by signaling pathways that regulate lineage-specific transcription factors and chromatin modifications guiding long-term gene expression programs. The chromatin landscape is altered chiefly by DNA or histone modifications, chromatin remodelers, and non-coding RNAs. Amongst histone modifiers, several studies have identified Polycomb group (PcG) proteins as crucial determinants mediating transcriptional repression of genes involved in developmental processes. Although PcG-mediated chromatin modifications define cellular transitions and influence cell identity of multipotent progenitors, much remains to be understood regarding coordination between extracellular signals and their impact on Polycomb functions during the pancreas lineage progression. In this review, we discuss interactions between sequence-specific DNA binding proteins and chromatin regulators underlying pancreas development and insulin producing β-cells, with particular focus on Polycomb group proteins. Understanding such basic molecular mechanisms would improve current strategies for stem cell-based differentiation while also help elucidate the pathogenesis of several pancreas-related maladies, including diabetes and pancreatic cancer.Copyright © 2018. Published by Elsevier B.V.