Previous investigations into potential transforming activities of adenovirus (Ad) early genes were largely overshadowed by the more obvious roles of E1A and E1B products. One exception was an Ad9 E4 protein (ORF1) shown to enhance transformation of cultured cells and promote mammary tumors in female rats. Recently, significant advances in understanding Ad E4 gene products at the molecular level have revealed that these proteins possess an unexpectedly diverse collection of functions, which not only orchestrate many viral processes, but overlap with oncogenic transformation of primary mammalian cells. Operating through a complex network of protein interactions with key viral and cellular regulatory components, Ad E4 products are apparently involved in transcription, apoptosis, cell cycle control, DNA repair, cell signaling, posttranslational modifications and the integrity of nuclear multiprotein complexes known as PML oncogenic domains (PODs). Some of these functions directly relate to known transforming and oncogenic processes, or implicate mechanisms such as modulating the function and subcellular localization of cellular PDZ domain-containing proteins, POD reorganization, targeted proteolytic degradation, inhibition of DNA double-strand break repair and 'hit-and-run' mutagenesis. Here, we summarize the recent data and discuss how E4 gene product interactions may contribute to viral oncogenesis.