The endocrine and exocrine pancreas have been studied separately by endocrinologists and gastroenterologists as two organ systems. The pancreatic islet, consisting of 1–2% mass of the whole pancreas, has long been believed to be regulated independently from the surrounding exocrine tissues. Particularly, islet blood flow has been consistently illustrated as one-way flow from arteriole(s) to venule(s) with no integration of the capillary network between the endocrine and exocrine pancreas. It is likely linked to the long-standing dogma that the rodent islet has a mantle of non–β-cells and that the islet is completely separated from the exocrine compartment. A new model of islet microcirculation is built on the basis of analyses of in vivo blood flow measurements in mice and an in situ three-dimensional structure of the capillary network in mice and humans. The deduced integrated blood flow throughout the entire pancreas suggests direct interactions between islet endocrine cells and surrounding cells as well as the bidirectional blood flow between the endocrine and exocrine pancreas, not necessarily a unidirectional blood flow as in a so-called insuloacinar portal system. In this perspective, we discuss how this conceptual transformation could potentially affect our current understanding of the biology, physiology, and pathogenesis of the islet and pancreas.