At the dawn of the 21st century, our knowledge of the molecular mechanism of mammalianfertilization remains very limited. Different lines of evidence indicate that initial gamete recognitiondepends on interaction between a few distinct proteins on sperm and ZP3, a major component of theextracellular coat of oocytes, the zona pellucida (ZP). On the other hand, recent findings suggest analternative mechanism in which cleavage of another ZP subunit, ZP2, regulates binding of gametesby altering the global structure of the ZP. Progress in the field has been hindered by the paucity andheterogeneity of native egg-sperm recognition proteins, so that novel approaches are needed toreconcile all available data into a single consistent model of fertilization. Following our recentdetermination of the structure of the most conserved domain of sperm receptor ZP3 by X-raycrystallography, we will conclusively establish the basis of mammalian gamete recognition byperforming structural studies of homogeneous, biologically active recombinant proteins. First, wewill combine crystallographic studies of isolated ZP subunits with electron microscopy analysis oftheir filaments to build a structural model of the ZP. Second, structures of key egg-spermrecognition protein complexes will be determined. Third, we will investigate how proteolysis ofZP2 triggers overall conformational changes of the ZP upon gamete fusion. Together withfunctional analysis of mutant proteins, these studies will provide atomic resolution snapshots of themost crucial step in the beginning of a new life, directly visualizing molecular determinantsresponsible for species-restricted gamete interaction at fertilization. The progressive decrease ofbirths in the Western world and inadequacy of current contraceptive methods in developingcountries underscore an urgent need for a modern approach to reproductive welfare. This researchwill not only shed light on a truly fundamental biological problem, but also constitute a solidfoundation for the reproductive medicine of the future.