The explosive increase in Ca2+ that occurs in the cytosol at fertilization is brought about by the activation of Ca2+-release channels in the intracellular stores. Inositol 1,4,5-trisphosphate (InsP3) is traditionally considered to be the messenger that initiates the increase and spreading of the activating Ca2+ wave. In line with this hypothesis, recent evidence suggests that the penetrating sperm delivers into mammalian eggs a novel isoform of phospholipase C (PLC), which promotes the formation of InsP3. By contrast, data from echinoderms studies indicate that the newly discovered second messenger nicotinic adenine dinucleotide phosphate (NAADP) promotes an initial, localized increase in Ca2+, which is then followed by the InsP3-mediated globalization of the Ca2+ wave. The mechanism by which the interacting sperm triggers the production of NAADP and subsequently that of InsP3 remains obscure.