Calcium-independent phospholipase A2 (iPLA2) belongs to the group VI family of phospholipase superfamily (PLA2) that catalyses the hydrolysis of glycerophospholipids at the sn-2 ester bond, producing unesterified fatty acids and 2-lysophospholipids. Research interests on iPLA2 have not been as significant as those on secretary PLA2 and cytosolic PLA2. However, more efforts have been made recently on understanding the expression, regulation and biological function of iPLA2. iPLA2 plays important roles in several biological processes, including signal transduction, phospholipid remodelling, eicosanoid formation, cell proliferation, cell differentiation and apoptosis. Modulation of iPLA2 activity can have prominent effects on cellular metabolism, central nervous system and cardiovascular functions. Thus, dysregulation iPLA2 can play a vital role in the pathogenesis of several diseases. The aim of this review is to provide the current understanding of the structure, function and regulation of group VI iPLA2 and highlight its potential mechanisms of action in mediating several neurological disorders and cancer. © 2016, Tianjin University and Springer-Verlag Berlin Heidelberg.