The human sperm acrosome reaction (AR) appears to be analogous to various somatic cell exocytotic events. The AR can be induced in vitro by naturally occurring and synthetic compounds, such as, human periovulatory follicular fluid (hFF) and calcium ionophore A23187. The events that culminate in the AR appear to involve at least two second messenger pathways. One pathway involves the generation of the second messenger adenosine 3':5'-cyclic monophosphate (cAMP) by the amplifying enzyme adenylate cyclase and leading to the activation of cAMP-dependent kinase (PKA). The effect of PKA stimulators, such as, forskolin and cAMP analogues, on AR was tested and they were found to stimulate the AR. Inhibitors of specific components in the PKA pathway, e.g. adenosine analogues and PKA inhibitors, induced dose-dependent reductions in the AR. Furthermore, naturally occurring agonists, including, hFF and solubilized human zona pellucida (sZP), in combination with PKA inhibitors, led to a significantly lower AR. Collectively, these data provide strong support for the role of the PKA pathway in the AR.