The E1B 55-kDa and E4 Orf6 proteins of human subgroup C adenoviruses both counter host cell defenses mediated by the cellular p53 protein and regulate viral late gene expression. A complex containing the two proteins has been implicated in induction of selective export of viral late mRNAs from the nucleus to the cytoplasm, with concomitant inhibition of export of the majority of newly synthesized cellular mRNAs. The molecular mechanisms by which these viral proteins subvert cellular pathways of nuclear export are not yet clear. Here, we review recent efforts to identify molecular and biochemical functions of the E1B 55-kDa and E4 Orf6 proteins required for regulation of mRNA export, the several difficulties and discrepancies that have been encountered in studies of these viral proteins, and evidence indicating that the reorganization of the infected cell nucleus and production of viral late mRNA at specific intra-nuclear sites are important determinants of selective mRNA export in infected cells. In our view, it is not yet possible to propose a coherent molecular model for regulation of mRNA export by the E1B 55-kDa and E4 Orf6 proteins. However, it should now be possible to address specific questions about the roles of potentially relevant properties of these viral proteins.