Polyspermy is penetration of the egg cytoplasm by more than a single spermatozoon, and in humans, polyspermy usually results in spontaneous abortion. Following sperm penetration in mammals, cortical granules (CGs), special organelles in eggs, release their contents into the perivitelline space. The CG exudates act on the zona pellucida, causing biochemical and structural changes that result in zona sperm receptor modification and zona hardening, and thus block polyspermic penetration. Significant advances have been made in elucidating signal molecules and signal transduction cascades that play important roles in the CG exocytosis and subsequent polyspermy block. Ca² oscillation is necessary and sufficient for CG exocytosis as well as for other events of egg activation. The Ca² -dependent pathways and the proteins involved in membrane fusion may play pivotal roles in the regulation of CG exocytosis. Mammalian oocytes develop their ability to undergo CG exocytosis during maturation. This article reviews the signal molecules and signal transduction cascades involved in CG exocytosis.