Freshly ejaculated spermatozoa are incapable or poorly capable of fertilizing an oocyte. The fertilization aptness of spermatozoa depends on the appropriate and time-dependent acquisition of hyperactivation, chemotaxis, capacitation, and the acrosome reaction, where calcium (Ca(2+)) is extensively involved in almost every step. A literature review showed that several ion channel proteins are likely responsible for regulation of the Ca(2+) uptake in spermatozoa. Therefore, manipulation of the functions of channel proteins is closely related to Ca(2+) influx, ultimately affecting male fertility. Recently, it has been shown that, together with different physiological stimuli, protein-protein interaction also modifies the Ca(2+) influx mechanism in spermatozoa. Modern proteomic analyses have identified several sperm proteins, and, therefore, these findings might provide further insight into understanding the Ca(2+) influx, protein functions, and regulation of fertility. The objective of this review was to synthesize the published findings on the Ca(2+) influx mechanism in mammalian spermatozoa and its implications for the regulation of male fertility in the context of sperm proteins. Finally, Pathway Studio (9.0) was used to catalog the sperm proteins that regulate the Ca(2+) influx signaling by using the information available from the PubMed database following a MedScan Reader (5.0) search.