Adenoviruses (Ads) are nonenveloped viruses which replicate and assemble in the nucleus. Therefore, viral membrane proteins are not directly required for their multiplication. Yet, all human Ads encode integral membrane proteins in the early transcription unit 3 (E3). Previous studies on subgenus C Ads demonstrated that most E3 proteins exhibit immunomodulatory functions. In this review we focus on the E3 membrane proteins, which appear to be primarily devoted to remove critical recognition structures for the host immune system from the cell surface. The molecular mechanism for removal depends on the E3 protein involved: E3/19K prevents expression of newly synthesized MHC molecules by inhibition of ER export, whereas E3/10.4–14.5K down-regulate apoptosis receptors by rerouting them into lysosomes. The viral proteins mediating these processes contain typical transport motifs, such as KKXX, YXXФ, or LL. E3/49K, another recently discovered E3 protein, may require such motifs to reach a processing compartment essential for its presumed immunomodulatory activity. Thus, E3 membrane proteins exploit the intracellular trafficking machinery for immune evasion. Conspicuously, many E3 membrane proteins from Ads other than subgenus C also contain putative transport motifs. Close inspection of surrounding amino acids suggests that many of these are likely to be functional. Therefore, Ads might harbor more E3 proteins that exploit intracellular trafficking pathways as a means to manipulate immunologically important key molecules. Differential expression of such functions by Ads of different subgenera may contribute to their differential pathogenesis. Thus, an unexpected link emerges between viral manipulation of intracellular transport pathways and immune evasion.