Following fusion of sperm and egg, the contents of cortical granules (CG), a kind of special organelle in the egg, release into the perivitelline space (cortical reaction), causing the zona pellucida to become refractory to sperm binding and penetration (zona reaction). Accumulating evidence demonstrates that mammalian cortical reaction is probably mediated by activation of the inositol phosphate (PIP₂) cascade. The sperm‐egg fusion, mediated by GTP‐binding protein (G‐protein), may elicit the generation of two second messengers, inositol 1,4,5 triphosphate (IP₃) and diacylglycerol (DAG). The former induces Ca²⁺ release from intracellular stores and the latter activates protein kinase C (PKC), leading to CG exocytosis. Calmodulin‐dependent kinase II (CaMKII) may act as a switch in the transduction of the calcium signal. The CG exudates cause zona sperm receptor modification and zona hardening, and thus block polyspermic penetration. Oolemma modification after sperm‐egg fusion and formation of CG envelope following cortical reaction also contribute to polyspermy block. Microsc. Res. Tech. 61:342–348, 2003. © 2003 Wiley‐Liss, Inc.