Herpesvirus saimiri (HVS) is the prototype gamma-2 herpesvirus and is a useful model to study the basic mechanisms of lytic replication in this herpesvirus subfamily. This review focuses upon the role of an essential lytic protein, ORF57, which is functionally conserved in all classes of herpesviruses. ORF57 is a multidomain, multifunctional protein responsible for both activation and repression of viral gene expression at a post-transcriptional level. ORF57-mediated repression of gene expression is determined by mRNA processing signals, in particular the presence of an intron within the target gene. This may also be linked to the ability of ORF57 to redistribute SC-35 and U2 splicing factors into specific nuclear domains. ORF57 also plays a pivotal role in transactivating viral gene expression by specifically mediating the nuclear export of HVS intronless transcripts. ORF57 has the ability to shuttle between the nucleus and the cytoplasm, bind viral RNA and recruit cellular nuclear export proteins, such as hTREX components and TAP, onto the viral mRNA. This enables the efficient nuclear export and cytoplasmic accumulation of virus intronless mRNA.