Activation of transcription within the embryonic genome (EGA) after fertilization is a complex process requiring a carefully coordinated series of nuclear and cytoplasmic events, which collectively ensure that the two parental genomes can be faithfully reprogrammed and restructured before transcription occurs. Available data indicate that inappropriate transcription of some genes during the period of nuclear reprogramming can have long-term detrimental effects on the embryo. Therefore, precise control over the time of EGA is essential for normal embryogenesis. In most mammals, genome activation occurs in a stepwise manner. In the mouse, for example, some transcription occurs during the second half of the one-cell stage, and then a much greater phase of genome activation occurs in two waves during the two-cell stage, with the second wave producing the largest onset of de novo gene expression. Changes in nuclear structure, chromatin structure, and cytoplasmic macromolecular content appear to regulate these periods of transcriptional activation. A model is presented in which a combination of cell cycle-dependent events and both translational and posttranslational regulatory mechanisms within the cytoplasm play key roles in mediating and regulating EGA.