Fertilization triggers a rise in intracellular Ca 2+ concentration ([Ca 2+ ] i ) in the egg that initiates a series of events known as egg activation. These events include cortical granule exocytosis that establishes a block to polyspermy, resumption of meiosis, and recruitment of maternal mRNAs into polysomes for translation. Several calcium-dependent proteins, including calcium/calmodulin-dependent protein kinase II (CaMKII), have been implicated in egg activation. However, the precise role of CaMKII in mediating specific events of egg activation and the identity of the isoform(s) present in mouse eggs have not been unequivocally established. Through targeted deletion of the γ isoform of CaMKII, we find that CaMKIIγ is the predominant CaMKII isoform in mouse eggs and that it is essential for egg activation. Although CaMKIIγ −/− eggs exhibit a normal pattern of Ca 2+ oscillations after insemination and undergo cortical granule exocytosis, they fail to resume meiosis or to recruit maternal mRNAs. Surprisingly, we find that the recruitment of maternal mRNAs does not directly depend on CaMKII, but requires elevated [Ca 2+ ] i and metaphase II exit. We conclude that CaMKIIγ specifically controls mouse egg activation by regulating cell cycle resumption.T he transition from a fertilization-competent mammalian egg to a developing embryo entails a sequence of events collectively known as egg activation. Early events of egg activation include modifications of the zona pellucida (ZP) that prevent polyspermy, exit from metaphase II arrest, and completion of meiosis, whereas late events include recruitment of maternal mRNAs into polysomes for translation and formation of male and female pronuclei (1). In all animal species studied to date, a rise in intracellular calcium ([Ca 2+ ] i ) is the universal trigger of all of the events of egg activation (EEA) (2). Release of a spermspecific phospholipase C isoform (PLCζ) likely initiates the inositol 1,4,5-trisphosphate (IP 3 )-mediated increase in [Ca 2+ ] i (3). In mammalian eggs, this increase in [Ca 2+ ] i takes the form of repetitive Ca 2+ transients (oscillations) that last several hours (4, 5). Although Ca 2+ oscillations can induce all of the EEA, individual events require different numbers of [Ca 2+ ] i transients to be initiated and completed, with early events requiring fewer oscillations than late events (6).The pathways that connect the rise in [Ca 2+ ] i to the different EEA have only been partially elucidated. Protein kinases, including calcium/calmodulin-dependent protein kinase II (CaM-KII), and the phosphatase calcineurin have been postulated as integrators of the Ca 2+ signal during egg activation (7-9). However, direct genetic evidence for involvement of these enzymes through loss-of-function studies is lacking, leaving open questions as to whether any single enzyme is essential for all of the EEA or whether these Ca 2+ -dependent events are mediated by different effectors.The CaMKII family of serine/threonine kinases mediates many cellular responses to C...