Progesterone is a physiological stimulus of human sperm acrosome reaction. The effects of the steroid, which is present in high levels in the cumulus matrix that surrounds the oocyte, are mediated by an increase of intracellular calcium concentrations, tyrosine phosphorylation of proteins, efflux of chloride and stimulation of activity of phospholipases. These effects are due to activation of a nongenomic pathway. Two different types of receptors for progesterone, distinct from the genomic ones, have been identified on the surface of human spermatozoa. We demonstrated that sperm responsiveness to progesterone is impaired in subfertile patients and that is strictly correlated to the ability of fertilize the oocyte. In addition, the determination of sperm responsiveness is predictive of fertilizing ability with a positive predictive value of 90% and can be clinically useful for the preliminary assessment of the male partner to select the appropriate assisted reproductive technique.