Islets produce a variety of cytokines and chemokines in response to physiologic and pathologic stimulation by nutrients. The cellular source of these inflammatory mediators includes α-, β-, endothelial-, ductal- and recruited immune cells. Islet-derived cytokines promote α- and β-cell adaptation and repair in the short term. Eventually, chronic metabolic stress can induce a deleterious autoinflammatory process in islets leading to insulin secretion failure and type 2 diabetes. Understanding the specific role of islet derived cytokines and chemokines has opened the door to targeted clinical interventions aimed at remodeling islet inflammation from destruction to adaptation. In this article, we review the islet cellular origin of various cytokines and chemokines and describe their regulation and respective roles in physiology and diabetes.