The group IV phospholipase A₂ (PLA₂) family is comprised of six intracellular enzymes (GIVA, -B, -C, -D, -E, and -F) commonly referred to as cytosolic PLA₂ (cPLA₂)α, -β, -γ, -δ, -ε, and -ζ. They contain a Ser-Asp catalytic dyad and all except cPLA₂γ have a C2 domain, but differences in their catalytic activities and subcellular localization suggest unique regulation and function. With the exception of cPLA₂α, the focus of this review, little is known about the in vivo function of group IV enzymes. cPLA₂α catalyzes the hydrolysis of phospholipids to arachidonic acid and lysophospholipids that are precursors of numerous bioactive lipids. The regulation of cPLA₂α is complex, involving transcriptional and posttranslational processes, particularly increases in calcium and phosphorylation. cPLA₂α is a highly conserved widely expressed enzyme that promotes lipid mediator production in human and rodent cells from a variety of tissues. The diverse bioactive lipids produced as a result of cPLA₂α activation regulate normal physiological processes and disease pathogenesis in many organ systems, as shown using cPLA₂α KO mice. However, humans recently identified with cPLA₂α deficiency exhibit more pronounced effects on health than observed in mice lacking cPLA₂α, indicating that much remains to be learned about this interesting enzyme.