The endocrine pancreas consists of highly vascularized and innervated endocrine mini-organs--the islets of Langerhans. These contain multiple types of hormone-producing cells, including the insulin-secreting beta-cell. The major task of the fully differentiated beta-cell is the tight regulation of blood glucose levels by secreting insulin into the blood stream. This requires molecular features to measure glucose and produce, process, and release insulin by exocytosis. Now multiple interactions with endocrine and nonendocrine islet cells as well as with other organs have been shown to affect the developing as well as the mature beta-cell. Therefore, failure of any of these interactions can inhibit beta-cell differentiation and glucohomeostasis. Here we review recent reports on intrapancreatic cell-cell interactions as well as signals derived from extrapancreatic organs that affect the pancreatic beta-cell.