Although the broad concepts of fertilisation are well defined, our understanding of the biochemical mechanisms underlying sperm-egg binding is limited. Early studies of fertilisation in the mouse implicated beta-1,4-galactosyltransferase-1 (GalT) as a sperm receptor for oligosaccharide ligands on the zona pellucida glycoprotein, ZP3. Binding of multiple ZP3 oligosaccharides induces GalT aggregation, leading to G-protein activation and initiation of the acrosome reaction. Consistent with this, GalT-null sperm show greatly reduced binding to ZP3 and are unable to undergo a zona-induced acrosome reaction. However, unexpectedly, GalT-null sperm are still able to bind to the intact zona pellucida. These and other studies indicate that sperm-egg binding requires at least two distinct molecular events: a GalT/ZP3-independent interaction that mediates initial gamete adhesion, followed by ZP3-dependent aggregation of GalT leading to acrosomal exocytosis. In this regard, recent studies have identified novel components of both sperm and eggs that are derived from reproductive tract secretions and which appear to participate in initial sperm-egg adhesion. SED1, also known as MFG-E8 and lactadherin, is secreted by the initial segment of the epididymis where it intercalates into the sperm plasma membrane and plays a critical role during spermzona binding. Similarly, an oviduct-derived glycoprotein has been identified that coats the zona pellucida of ovulated eggs and which has sperm-binding activity. The realization that successful sperm-egg binding results from the sequential action of molecularly distinct events may account for the large number of components that have been implicated in sperm-egg interactions, as well as why it has been difficult to reach a consensus regarding the underlying molecular mechanisms.