To achieve successful fertilization under normal circumstances in vivo, mammalian spermatozoa must first undergo capacitation and then the acrosome reaction, an exocytotic event that allows cells to penetrate the zona pellucida and fuse with the oocyte plasma membrane. These complex events permit spermatozoa to achieve fertilizing ability at the right time in the right place, important considerations since relatively few sperm cells actually reach the site of fertilization in vivo. Several mechanisms that may be involved in regulating the acquisition of fertilizing ability are considered. In vivo, selective pressures placed on the initial population of spermatozoa help ensure that the 'fittest' spermatozoa are able to fertilize. Since intracytoplasmic sperm injection bypasses this selection process, it is best used only in cases where spermatozoa are judged to be incapable of achieving normal fertilization in vitro.