Herpesviruses are enveloped viruses with large double-stranded DNA genomes that are highly prevalent in the human population and elicit numerous types of clinical manifestations, from mild to severe. These viruses are classified into three subfamilies: alpha-, beta-, and gammaherpesvirinae, all capable of establishing life-long persistent infections in the host. As strict intracellular parasites, these viruses have evolved molecular determinants to support and modulate viral and host gene transcription processes during infection and the translation of messenger RNAs (mRNAs) to synthesize proteins that participate in cellular pathways promoting their replication cycles and virion formation. Notably, some of these proteins have functional RNA-binding domains consisting of arginine-glycine-glycine (RGG) amino acid (aa) sequences that, when methylated, regulate their nucleic acid-binding capacities and can influence the export of mRNAs lacking introns from the nucleus into the cytoplasm. Additional domains and motifs in these proteins mediate their interactions with regulatory proteins related to RNA splicing, either promoting or repressing mRNA processing. Notably, all human herpesviruses (HHVs) encode in their genomes proteins that share homology with infected cell protein 27 (ICP27) of herpes simplex virus type 1 (HSV-1), which can significantly impact the biogenesis of mRNAs and their processing during infection. Here, we review and discuss the roles of ICP27 and the corresponding homologs encoded in different human herpesviruses, focusing on their similarities and differences in structure and function. A more profound knowledge of the role of key viral factors required for effective herpesvirus replication could aid in the design and identification of novel antivirals to treat the diseases produced by these viruses.