A20 is most characteristically described in terms relating to inflammation and inflammatory pathologies. The emerging understanding of inflammation in the etiology of diabetes mellitus lays the framework for considering a central role for A20 in this disease process. Diabetes mellitus is considered a major health issue, and describes a group of common metabolic disorders pathophysiologically characterized by hyperglycemia. Within islets of Langherhans, the endocrine powerhouse of the pancreas, are the insulin-producing pancreatic beta-cells. Loss of beta-cell mass and function to inflammation and apoptosis is a major contributing factor to diabetes. Consequently, restoring functional beta-cell mass via transplantation represents a therapeutic option for diabetes. Unfortunately, transplanted islets also suffers from loss of beta-cell function and mass fueled by a multifactorial inflammatory cycle triggered by islet isolation prior to transplantation, the ischemic environment at transplantation as well as allogeneic or recurrent auto-immune responses. Activation of the transcription factor NF-kappaB is a central mediator of inflammatory mediated beta-cell dysfunction and loss. Accordingly, a plethora of strategies to block NF-kappaB activation in islets and hence limit beta-cell loss have been explored, with mixed success. We propose that the relatively poor efficacy of NF-kappaB blockade in beta-cells is due to concommittant loss of the important, NF-kappaB regulated anti-apoptotic and anti-inflammatory protein A20. A20 has been identified as a beta-cell expressed gene, raising questions about its role in beta-cell development and function, and in beta-cell related pathologies. Involvement of apoptosis, inflammation and NF-kappaB activation as beta-cell factors contributing to the pathophysiology of diabetes, coupled with the knowledge that beta-cells express the A20 gene, implies an important role for A20 in both normal beta-cell biology as well as beta-cell related pathology. Genome wide association studies (GWAS) linking single nucleotide polymorphisms in the A20 gene with the occurrence of diabetes and its complications support this hypothesis. In this chapter we review data supporting the role of A20 in beta-cell health and disease. Furthermore, by way of their specialized function in metabolism, pancreatic beta-cells also provide opportunities to explore the biology of A20 in scenarios beyond inflammation.