A survey of species differences in the duration of capacitation, T, has revealed that they closely correlate with sperm cholesterol/phospholipid mole ratios, R : T = 8R - 1 (r2 = 0.97, in which r is Pearson's correlation coefficient). Because uterine cells displayed low relative cholesterol concentrations, spermatozoa evidently experience a negative external cholesterol gradient (positive phospholipid gradient) during capacitation. A decrease in sperm R-value is suggested, therefore, to accompany capacitation. The idea received strong support from a kinetic analysis of capacitation intervals, based on the rate of cholesterol efflux from sperm cells in utero. Lipid-binding serum proteins in uterine fluid are attributed with removing a sterol barrier to the Ca2+-facilitated membrane fusion that initiates the acrosome reaction. Tight cell junctions prevent permeation of the male generative tract by these proteins (capacitation factors). Furthermore, seminal plasma contains a decapacitation factor, identified as a membrane vesicle (cholesterol donor) component of this fluid, that reverses capacitation. Initiation of the sperm acrosome reaction among mammals could be the first fusion process found to be physiologically modulated through the membrane bilayer cholesterol level.