Gamete membrane interactions begin with adhesion (binding) of the sperm to the oocyte plasma membrane and culminate with fusion of the membranes of the gametes, thus creating the zygote through the union of these two very different cells. This review summarizes the molecular and cell biology of the cell-cell interactions between mammalian gametes. Recent research studies have provided new insights into the complexity of these interactions and into the importance of multimeric molecular networks and optimal membrane order in both sperm and oocytes for successful fertilization. Molecules that will be highlighted include cysteine-rich secretory protein 1 (CRISP1) and ADAMs [fertilin alpha (ADAM1), fertilin beta (ADAM2) and cyritestin (ADAM3)] on sperm, and integrins, CD9, and other integrin-associated proteins on oocytes, as well as other molecules. The characteristics of these gamete molecules are summarized, followed by discussions of the experimental data that provide evidence for their participation in gamete membrane interactions, and also of the specific roles that these molecules might play. Insights from a variety of research areas, including gamete biology, cell adhesion, and membrane fusion, are put together for a tentative model of how sperm-oocyte adhesion and fusion occur. The clinical relevance of correct gamete membrane interactions is also noted.