Sperm-egg fusion is a cell-cell membrane fusion event essential for the propagation of sexually reproducing organisms. In gamete fusion, as in other fusion events, such as virus-cell and intracellular vesicle fusion, membrane fusion is a two-step process. Attachment of two membranes through cell-surface molecules is followed by the physical merger of the plasma membrane lipids. Recent progress has demonstrated an essential role for an oocyte tetraspanin, CD9, in mouse sperm-egg fusion, and a specific molecular site crucial for CD9 function has been identified. Absence of glycosylphosphatidylinositol-anchored proteins on the oocyte surface also results in loss of oocyte fusion competence in this gamete. These discoveries provide a strong starting point for the identification of additional proteins that have roles in sperm-egg fusion.