Oocyte activation is a calcium (Ca²⁺)-dependent process that has been investigated in depth, in particular, regarding its impact on assisted reproduction technology (ART). Following a standard model of signal transduction, Ca²⁺drives the meiotic progression upon fertilization in all species studied to date. However, Ca²⁺changes during oocyte activation are species specific, and they can be classified in two modalities based on the pattern defined by the Ca²⁺signature: a single Ca²⁺transient (e.g. amphibians) or repetitive Ca²⁺transients called Ca²⁺oscillations (e.g. mammals). Interestingly, assisted oocyte activation (AOA) methods have highlighted the ability of mammalian oocytes to respond to single Ca²⁺transients with normal embryonic development. In this regard, there is evidence supporting that cellular events during the process of oocyte activation are initiated by different number of Ca²⁺oscillations. Moreover, it was proposed that oocyte activation and subsequent embryonic development are dependent on the total summation of the Ca²⁺peaks, rather than to a specific frequency pattern of Ca²⁺oscillations. The present review aims to demonstrate the complexity of mammalian oocyte activation by describing the series of Ca²⁺-linked physiological events involved in mediating the egg-to-embryo transition. Furthermore, mechanisms of AOA and the limitations and benefits associated with the application of different activation agents are discussed.