It is intriguing that the disruption of a number of genes, e.g., Clgn, Ace, Adamla, Adam2 and Adam3 results in a similar sperm phenotype, i.e., failure of sperm to bind to the zona pellucida (ZP). Because calmegin functions as a testis-specific molecular chaperone, there is a possibility of misfolding of ADAMs in sperm from Clgn-/- mice. In the first half of this review we describe the interaction of ADAMs with calmegin and try to elucidate the relationship of these proteins to establish the zona binding ability. In the second half of this review we describe other gene manipulated animals that lead to a defect in sperm-egg fusion. The first factor, CD9, was found serendipitously on the egg side, while the second factor, Izumo, on the sperm side, was discovered after 20 years of pursuit. Here we describe various gene manipulated animals that are useful to elucidate the mechanism of fertilisation.