This review shows that phospholipases belonging to different families (PLA, PLC, and PLD) play a pivotal role in the regulation of cell signaling in brain tumors and are consequently implicated in the pathogenetic and clinical evolution of low- and high-grade gliomas as tumor suppressors or oncogene, thus proving to be attractive prognostic biomarkers or therapeutic targets, respectively, for these heterogeneous tumors with no real effective cure. This evidence concerns the gene HSPG2 and central nervous system cancer.