Mammalian sperm cells must respond to cues originating from along the female reproductive tract and from the layers of the egg in order to complete their fertilization journey. Dynamic regulation of ion signalling is, therefore, essential for sperm cells to adapt to their constantly changing environment. Over the past 15 years, direct electrophysiological recordings together with genetically modified mouse models and human genetics have confirmed the importance of ion channels, including the principal Ca2+-selective plasma membrane ion channel CatSper, for sperm activity. Sperm ion channels and membrane receptors are attractive targets for both the development of contraceptives and infertility treatment drugs. Furthermore, in this era of assisted reproductive technologies, understanding the signalling processes implicated in defective sperm function, particularly those arising from genetic abnormalities, is of the utmost importance not only for the development of infertility treatments but also to assess the overall health of a patient and his children. Future studies to improve reproductive health care and overall health care as a function of the ability to reproduce should include identification and analyses of gene variants that underlie human infertility and research into fertility-related molecules.