Replication of human retroviruses, such as the human immunodeficiency virus type 1 (HIV-1) and the human T-cell leukemia virus type 1 (HTLV-1), depends on the transport of subgenomic mRNAs and unspliced genomic RNA from the nucleus to the cytoplasm. This nuclear RNA export is promoted by two small viral regulatory proteins, termed Rev in HIV-1 and Rex in HTLV-1. Both Rev and Rex interact with multiple cellular proteins in order to translocate viral RNA across the nuclear envelope and are considered to be model systems in which to study the regulation of nuclear export. In particular. Rev’s function in nuclear export has been discussed as part of multiple general reviews on nucleocytoplasmic trafficking (Stutz and Rosbash 1998; Izaurralde and Adam 1998; Nakielny and Dreyfuss 1999; GÖrlich and Kutay 1999). Moreover, an excellent and comprehensive review on the various aspects of HIV-1 Rev trans-activation has already been published (Pollard and Malim 1998). Instead of reiterating these data, in this chapter I would like to focus mainly on the various interactions of Rev and Rex with potential cellular cofactors. In addition, I would also like to explore some unresolved questions with respect to Rev/Rex function