Activation of phospholipases A2 (PLA2s) leads to the generation of biologically active lipid mediators that can affect numerous cellular events. The Group VIA Ca2+-independent PLA2, designated iPLA2β, is active in the absence of Ca2+, activated by ATP, and inhibited by the bromoenol lactone suicide inhibitor (BEL). Over the past 10-15 years, studies using BEL have demonstrated that iPLA2β participates in various biological processes and the recent availability of mice in which iPLA2β expression levels have been genetically-modified are extending these findings. Work in our laboratory suggests that iPLA2β activates a unique signaling cascade that promotes β-cell apoptosis. This pathway involves iPLA2β dependent induction of neutral sphingomyelinase, production of ceramide, and activation of the intrinsic pathway of apoptosis. There is a growing body of literature supporting β-cell apoptosis as a major contributor to the loss of β-cell mass associated with the onset and progression of Type 1 and Type 2 diabetes mellitus. This underscores a need to gain a better understanding of the molecular mechanisms underlying β-cell apoptosis so that improved treatments can be developed to prevent or delay the onset and progression of diabetes mellitus. Herein, we offer a general review of Group VIA Ca2+-independent PLA2 (iPLA2β) followed by a more focused discussion of its participation in β-cell apoptosis. We suggest that iPLA2β-derived products trigger pathways which can lead to β-cell apoptosis during the development of diabetes. © 2010.