Fertilization and certain later stages in mammalian embryonic development require fusion between membranes of individual cells. The mechanism of eukaryotic cell-cell fusion is unknown, and no surface molecules required for this process have been unequivocally identified. The role of the sperm surface protein fertilin in sperm-egg fusion was tested by using peptide analogues of a potential integrin binding site in the fertilin beta subunit. Peptide analogues that include a TDE sequence from the disintegrin region of fertilin beta are able to bind to the egg plasma membrane and strongly inhibit sperm-egg fusion. These results show that the disintegrin domain of fertilin beta binds to the egg plasma membrane and that this binding is required for membrane fusion.