Accurate cellular localization is crucial for the effective function of most viral macromolecules and nuclear translocation is central to the function of herpesviral proteins that are involved in processes such as transcription and DNA replication. The passage of large molecules between the cytoplasm and nucleus, however, is restricted, and this restriction affords specific mechanisms that control nucleocytoplasmic exchange. In this review, we focus on two cytomegalovirus-encoded proteins, pUL69 and pUL84, that are able to shuttle between the nucleus and the cytoplasm. Both viral proteins use unconventional interactions with components of the cellular transport machinery: pUL69 binds to the mRNA export factor UAP56, and this interaction is crucial for pUL69-mediated nuclear export of unspliced RNA; pUL84 docks to importin-alpha proteins via an unusually large protein domain that contains functional leucine-rich nuclear export signals, thus serving as a complex bidirectional transport domain. Selective interference with these unconventional interactions, which disturbs the intracellular trafficking of important viral regulatory proteins, may constitute a novel and attractive principle for antiviral therapy.