A decrease in both mass and secretory function of insulin producing beta cells contribute to the pathophysiology of type 1 and type 2 diabetes. In this chapter, we review the evidence that glucose, inflammation, dyslipidemia, leptin, autoimmunity, amyloid and some sulfonylureas may contribute to the maladaptation of beta cells. With respect to these causal factors, we focus on IL-1beta, Fas, IRS-2, oxidative stress, NF-kappaB, ER stress, mitochondrial dysfunction, and the K_ATP-channel as potential mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of beta-cell secretory function and cell turnover. To this end, we believe the mechanisms regulating beta-cell proliferation, apoptosis and function are inseparable processes.