Human semen is ejaculated into the anterior vagina and, within minutes, spermatozoa enter the cervix by traversing the cervical mucus. Human sperm capacitation is initiated when the male gamete traverses the cervical mucus, with the removal of inhibitory factors from the seminal plasma. Studies performed in several mammalian species have shown that sperm cells that have completed capacitation first bind to the zona pellucida (ZP) and undergo acrosomal exocytosis (AE). Acrosome-reacted spermatozoa penetrate the ZP, reach the perivitelline space, and bind and fuse to the egg plasma membrane. Sperm-ZP binding involves the interaction of ZP components with sperm surface proteins of capacitated cells, known as primary binding. The evaluation of the subfertile male should include a basic semen analysis, followed by bioassays aimed at assessing sperm functional competence. Many of the molecular mechanisms underlying mammalian sperm capacitation, AE, and fusion with the egg modulate somatic cell functions.