It has only been within the last few years that insights have been gained into the remarkable diversity of functions of the adenovirus early transcription region 4 (E4) products. The polypeptide encoded by E4 open reading frame 4 (E4orf4) has emerged as an enigmatic product. Although it accomplishes certain functions that propel viral replication, it has also been shown to be highly toxic, an effect that could dampen the infectious cycle, but that also might serve to facilitate release of viral progeny. When expressed alone, E4orf4 induces a novel form of p53-independent apoptosis in cancer cells but not in normal human cells, thus making it of potential use in cancer gene therapy. In addition, knowledge of its mechanism of action, especially with regard to its interaction with protein phosphatase 2A (PP2A), could provide insights to develop new small molecule anti-cancer drugs. Thus future studies on E4orf4 should be both informative and potentially valuable therapeutically. In this study we review the current status of knowledge on E4orf4.