An average human ejaculate contains over one hundred million sperm, but only a few succeed in accomplishing the journey to an egg by migration through the female reproductive tract. Among these few sperm, only one participates in fertilizing an egg. Surely there must be an ingenious molecular mechanism to ensure that the very best sperm succeed in fertilization. Recent gene manipulation approaches in mice have revealed that many factors previously described as important for fertilization are largely dispensable; however, novel factors are also emerging. For example, sperm from six different gene-disrupted mouse lines (Calmegin, Adam1a, Adam2, Adam3, Ace and Pgap1) are all known to have defective zona binding ability and at the same time lose oviduct migrating ability. Concerning gamete fusion, we found essential factors, IZUMO1 on sperm and CD9 on the egg, in genedisruption experiments. More recently, the structure, localization, and interacting proteins of IZUMO1 are gradually being elucidated. Besides IZUMO1, in non-mammal eukaryotes, fertilization-related proteins (GCS1 for plants and Sneaky for the fly) have been identified and reported to function in gamete interaction and fusion. This review focuses on the interactions of fusion-related proteins on sperm (the egg proteins will be discussed by Miyado et al.) of gene manipulated animals.