The development of the endocrine pancreas is regulated by several cell-matrix interactions that generate a diverse array of intracellular signals determining the progression of a multipotent progenitor to a mature endocrine cell. This process involves interactions between the epithelium, mesenchyma, and endothelial cells. Later in development, coordinated signaling contributes to the maintenance of the differentiated endocrine cell phenotype. It has been demonstrated that key factors as well as the sequence of events involved in mouse pancreatic development is conserved in humans. This review will discuss our current knowledge in mouse as well as human pancreatic development and highlights some important transcription factors associated with human disease.