During its productive infection, HSV-1 dramatically remodels the architecture and physiology of the host cell nucleus. The immediate-early proteins, the first viral proteins to be expressed during infection, are key players in this process. Here, we review the known properties and functions of immediate-early protein ICP22. Although this polypeptide has received less attention than other immediate-early proteins, the published evidence indicates that it mediates several striking changes to important host nuclear systems, including those involved in RNA polymerase II transcription, cell cycle regulation and protein quality control. Recent genetic analyses suggest that these alterations can promote HSV-1 productive infection. Thus, future work on ICP22 is likely to reveal novel mechanisms by which herpesviruses, and possibly other DNA viruses, manipulate the host cell nucleus to enhance their replication.