Although the endocrine component of the pancreas represents about less than 10% of the volume of the gland, it plays a crucial role in regulating the metabolic functions, mainly the glucose metabolism. The diseases affecting the endocrine pancreas lead to clinical pictures due to the increase or decrease of glucose blood levels. Pathology of the endocrine pancreas includes non-neoplastic and neoplastic diseases. Among the former, diabetes mellitus and persistent hyperinsulinemic hypoglycemia in infancy (PHHI) and adults (PHHA) are two pathologies due, respectively, to the increase or decrease of glucose blood level. Diabetes mellitus represents one of the most important metabolic pathology with increasing relevant social implications in industrialized countries, while persistent hyperinsulinemic hypoglycemia, although rather rare, can be difficult to diagnose and has important therapeutic implications, especially for children. Pancreatic endocrine tumors are a heterogeneous group of neoplasms showing different morphological, molecular, and clinical aspects. Although less frequent than tumors originating in the exocrine pancreas, their incidence is increasing due to modern and more sensitive imaging investigations. Conversely, due to exocrine cancers, surgical and medical therapies play an important therapeutic role with favorable influence on patients’ survival in the majority of cases. In the present chapter, we describe the main clinicopathological features of both non-neoplastic and neoplastic diseases affecting the endocrine pancreas. In addition, we make an update of the most relevant molecular aspects, which are involved in the pathogenesis of such diseases.