ABSTRACT: Human cytomegalovirus (HCMV), a member of the β-herpesvirus subfamily, is an important pathogen that infects the majority of the human population. The evolutionary success of HCMV largely depends on its ability to evade host defense systems and establish a lifelong persistence after primary infection. In fact, HCMV has dedicated a considerable part of its gene products to manipulate or disable immune effector processes. This review focuses on the major immediate–early protein IE1 – a multifunctional key regulator that has the capacity to counteract the first host defense activities. We summarize the known structural and mechanistic features by which IE1 modulates innate immune mechanisms as well as other cellular processes, and discuss how the individual functions of IE1 contribute to the success of a lytic HCMV infection.