More than 50 years ago Austin and Chang defined mammalian sperm capacitation as a period of time that sperm must reside in the female reproductive tract before they acquire the ability to fertilize oocytes. Since then numerous investigations have attempted to more clearly define the molecules and processes that are a part of capacitation. The data that have provided a more clear definition of capacitation were primarily derived from in vitro experiments. This is particularly true for studies on human sperm capacitation. While ethical constraints have limited an equal balance of in vivo studies there are those data that when coupled with some of the in vitro data allow for the formulation of a biological framework for human sperm capacitation in vivo. This review will put forth the biological basis for human capacitation.