Calcium ions (Ca2+) are involved in nearly every aspect of cellular life. They are one of the most abundant elements in mammals and play a vital role in physiological and biochemical processes acting mainly as intracellular messengers. In spermatozoa, several key functions are regulated by cytoplasmic Ca2+ concentration such as sperm capacitation, chemotaxis, hyperactive motility, and acrosome reaction. The sperm-specific ion channel CatSper is the principal calcium channel in sperm mediating the calcium influx into the sperm flagellum and acting as an essential modulator of downstream mechanisms involved in fertilization. This review aims to provide insights into the structure, localization, and function of the mammalian CatSper channel, primarily human and mice. The activation of CatSper by progesterone and prostaglandins, as well as the ligand-independent regulation of the channel by a change in the membrane voltage and intracellular pH are going to be addressed. Finally, major questions, challenges, and perspectives are discussed.