Abstract Fertilization in mammalian eggs is accompanied by oscillatory changes in intracellular Ca 2+ concentration, which are critical for initiating and completing egg activation events and the developmental program. Ca 2+/Camodulin-dependent protein kinase II (CaMKII) is a multifunctional enzyme that is postulated to be the downstream transducer of the Ca 2+ signal in many cell types. We tested the hypothesis that CaMKII is the major integrator of Ca 2+-induced egg activation events and embryo development by microinjecting a cRNA that encodes a constitutively active (Ca 2+-independent) mutant form of CaMKII (CA-CaMKII) into mouse eggs. Expression of this cRNA, which does not increase intracellular Ca 2+, induced a sustained rise in CaMKII activity and triggered egg activation events, including cell cycle resumption, and degradation and recruitment of maternal mRNAs; cortical granule exocytosis, however, did not occur normally. Furthermore, when mouse eggs were injected with sperm devoid of Ca 2+-releasing activity and activated with either CA-CaMKII cRNA or by SrCl 2, similar rates and incidence of development to the blastocyst stage were observed. These results strongly suggest that CaMKII is a major integrator of the Ca 2+ changes that occur following fertilization.