Progesterone (P) is one of the physiological stimuli of human sperm acrosome reaction. It is present in high levels at the site of fertilization (cumulus oophorus) and has been describe to affect several sperm functions including motility, capacitation and 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, efflux of chloride, stimulation of activity of phospholipases and phosphorylation of proteins. These effects are due to activation of a rapid/nongenomic pathway. Two different types of receptors for P, distinct from the genomic ones, have been recently identified on the surface of human spermatozoa. The affinities of P for these receptors are respectively in the nano- and in the micromolar range. Sperm responsiveness to progesterone is impaired in subfertile patients and 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.