The promise of the mouse model of cytomegalovirus (CMV) research lies in a cost effective way to obtain significant data in in vivo settings. Keeping that promise requires a high degree of equivalency in the human and mouse virus. While genomic structure and many common proteins suggest that this system is appropriate to develop and test concepts in an organismal context, areas of difference have not been evaluated. Here we show that the major immediate early protein 1 (IE1) in MCMV binds the repressor Daxx suggesting that it serves a function performed by pp71 in HCMV. A Daxx binding pp71 equivalent at M82 could not be identified for MCMV. Differences in the mouse and human interferon upregulation of Daxx may have driven the need to have a Daxx-defeating function during reactivation, when pp71 is not present. The major immediate early protein 1 also differs in its chromatin binding properties between the two viruses. MCMV IE1 does not bind to chromatin, but HCMV IE1 does. It remains unclear whether this difference is functionally significant. The HCMV major immediate early protein 2 and its MCMV equivalent IE3 differ in their effect on the cell cycle; HCMV IE2 blocks the cell cycle, but MCMV IE3 does not, allowing MCMV to spread in infected mouse cells by cell division with continued expression of the major transactivating viral proteins. Actively transcribing genomes inducing immediate transcript environments are usually silenced and diminish during cell cycle progression. However, a recognizable desilencing and increase in immediate transcript environments takes place immediately after mitosis in MCMV infected cells. This raises the possibility that desilencing happens during tissue transplantation, wound healing, or other injury where cells are induced to proliferate.