It is generally accepted that the presence of a presumably normal spermatozoon does not guarantee oocyte activation and fertilization, with some ICSI cycles constantly facing low fertilization if not complete fertilization failure. Both the sperm and the oocyte play an important role in oocyte activation and in case of physiological activation problems any artificial increase in ooplasmic calcium could rescue fertilization (irrespective of the causative gamete). Such an artificial Ca2+ increase can be achieved using modified ICSI techniques, piezoelectrical manipulation or chemical stimuli. Among these approaches the latter is currently the most accepted in IVF laboratories around the world, and the Ca2+-ionophores calcimycin and ionomycin are among the most extensively studied substances. Available neonatal and neurodevelopmental data indicate that ionophores can be considered safe, which may explain the steadily growing range of indications for application. However, as artificial oocyte activation rarely results in physiological Ca2+ oscillations and is not beneficial for all patients with a suspected activation deficiency, these techniques should not be used without profound indication.