The zona pellucida (ZP) is a glycoprotein matrix surrounding mammalian oocytes, critical for fertilization and early embryo development. ZP2. one of four major ZP glycoproteins (ZP1-4), plays a key role in sperm binding and the structural integrity of the ZP. Antibodies targeting ZP2 are primarily studied in reproductive immunology due to their association with infertility. In autoimmune or idiopathic infertility, anti-ZP2 antibodies may disrupt sperm-oocyte interaction by blocking ZP2’s sperm receptor function or altering ZP structure, impairing fertilization. These antibodies are also linked to premature ovarian insufficiency (POI), as ZP2 autoimmunity may trigger follicular atresia or oocyte apoptosis. Research in animal models shows that ZP2 immunization can induce infertility, supporting its contraceptive potential. Clinically, ZP2 antibodies are detected via immunoassays in women with unexplained infertility, though their diagnostic utility remains debated due to variable prevalence and heterogeneity in study populations. Recent studies explore ZP2’s epitope-specific immune responses, aiming to differentiate pathogenic antibodies from incidental biomarkers. Additionally, ZP2 antibodies are tools in basic research, helping elucidate ZP assembly and fertilization mechanisms. Despite progress, their exact pathophysiological role and therapeutic implications (e.g., immunocontraception or fertility preservation) require further investigation.