Fertilization is the process by which two terminally differentiated cells, the sperm and the egg, merge to form a totipotent cell, the zygote. This review addresses one of the culminating steps in getting sperm and egg together: the cell-cell interactions that allow the two gametes to fuse and create the zygote. Based on cell biological and genetic studies, major players include CD9 on the egg and Izumo on the sperm, although other molecules are part of an ever-evolving discussion of models for the molecular mechanisms leading to sperm-egg fusion, since few molecules have been shown to be completely essential for sperm-egg union. This sets the stage for consideration of how genetic approaches impact the field – of how knockout mouse reproductive phenotypes translate to humans and other animals and also of how interactions between redundant, nonessential genes could affect reproductive processes such as gamete interaction ("synthetic infertility," analogous to synthetic lethality). We will address these issues, examine the molecular basis of sperm-egg union and how this field has evolved with modern approaches combined with classical studies, and also discuss basic research in gamete biology in light of its possible application to reproductive health.