Successful mammalian fertilization, resulting in the formation of a diploid zygote from haploid gametes, requires a series of events that enable a sperm to reach and fuse with an oocyte. To become competent for fertilization, the sperm must first undergo capacitation, a process that is followed by the acrosome reaction. During the acrosome reaction, the acrosome, a membrane-bound organelle localized to the sperm head, fuses with the sperm’s plasma membrane and releases proteolytic enzymes that allow the sperm to penetrate the zona pellucida, an extracellular matrix surrounding the oocyte. After traveling through the zona pellucida, the sperm recognizes, binds to, and fuses with the oocyte plasma membrane, or the oolemma. This process is mediated by surface receptors on both the sperm and the oocyte. Once fertilization occurs, the oocyte blocks polyspermy by preventing additional sperm from accessing the oocyte. The oocyte undergoes a cortical reaction, in which cortical granules fuse with the oolemma to release enzymes that modify the zona pellucida, rendering it impermeable to the sperm entry. At the oolemma, the sperm–oocyte-binding capacity is reduced, preventing further sperm attachment.