Phospholipase A₂ is an important enzyme with many family members. As a special member of the phospholipase A₂ superfamily, secretory phospholipase PLA2G5 is expressed in both immune and non-immune cells. Studies have shown that PLA2G5 is tissue and cell specific, and its biological functions are even related to species and environment. Many researchers have studied PLA2G5 in humans as well as in transgenic and knockout mice, and have gained a deeper understanding of its biological and pathophysiological effects. The PLA2G5 gene is located on mouse chromosome 4 and human chromosome 1. It encodes a protein with a molecular mass of 14 ku, highly conserved Ca²⁺ binding loop and enzyme binding site, and contains only 6 disulfide bonds without specific sulfur bonds of group Ⅰand Ⅱ sPLA₂, N-terminal propetide, insertion and C-terminal extension. PLA2G5 has a variety of biological functions. It can not only bind to heparan sulfate proteoglycans through a cluster of negatively charged residues, but also bind to membrane phosphatidylcholine with high affinity, release arachidonic acid, initiate eicosanoid cascade reaction, and then conduct signal transduction. Meanwhile, it can help against pathogens, present antigens, serve as Th2/M2 to regulate the innate immune response, and play an anti-inflammatory or pro-inflammatory role in different immune diseases. In addition, PLA2G5 can effectively hydrolyze phospholipids in lipoproteins, which helps to control the quality of lipids and participate in lipid metabolism. PLA2G5 induces airway inflammatory diseases such as asthma and acute respiratory distress syndrome. It is closely related to cardiac homeostasis and can reduce the risk of aortic dissection, but it can also aggravate atherosclerosis and has dual effects on low density lipoprotein and perivascular fibrosis. It is a potential biomarker for detecting the progression of knee osteoarthritis and can trigger inflammatory response in rheumatoid arthritis. It can improve metabolic syndrome, fight against adipose tissue inflammation, insulin resistance, hyperlipidemia and obesity. It has antibacterial activity against Gram-positive bacteria, and Pla2g5^-/- mice are more sensitive to Candida albicans and Escherichia coli infection. Besides, mutations in PLA2G5 gene site 45 produce extra cysteine, causing conformational changes that lead to the development of benign familial retina macular disease. Mutation or overexpression of PLA2G5 can also affect the occurrence and development of human malignant tumors. Studies have shown that overexpression of PLA2G5 is a marker of poor prognosis for gliomas. A tumor mutation load model based on PLA2G5 gene can accurately predict the recurrence risk of ovarian cancer. Furthermore, several synthetic inhibitors, including silicon-directed recognition inhibitors of indole-amide-biphenyl derivatives, phospholipid analogs, and potential natural inhibitors such as olanolic acid syrenic oregano, have certain inhibitory effects on PLA2G5. These results provide theoretical bases for novel therapeutic approaches targeting PLA2G5.