Cyclin B1, the regulatory component of M phase-promoting factor (MPF), is degraded during the metaphase-anaphase transition in an anaphase-promoting complex/cyclosome (APC/C)-dependent process MPF activity is stable in eggs, and a sperm-triggered Ca²⁺ signal is needed to promote cyclin degradation. In frogs, a single Ca²⁺ spike promotes cell cycle resumption, but, in mammals, the Ca²⁺ signal is more complex, consisting of a series of spikes that stop several hours after sperm fusion. Using dual imaging in mouse eggs, we have examined how the Ca²⁺ signal generates cyclin B1 destruction using destructible and nondestructible GFP-tagged constructs. APC/C activity was present in unfertilized eggs, giving cyclin B1 a half-life of 1.15 ± 0.28 hr. However, APC/C-dependent cyclin degradation was elevated 6-fold when sperm raised cytosolic Ca²⁺ levels above 600 nM. This activation was transitory since cyclin B1 levels recovered between Ca²⁺ spikes. For continued cyclin degradation at basal Ca²⁺ levels, multiple spikes were needed. APC/C-mediated degradation was observed until eggs had completed meiosis with the formation of pronuclei, and, at this time, Ca²⁺ spikes stopped. Therefore, the physiological need for a repetitive Ca²⁺ signal in mammals is to ensure long-term cyclin destruction during a protracted exit from meiosis.