The homologous ETV1, ETV4 and ETV5 proteins form the PEA3 subfamily of ETS transcription factors. In Ewing tumors, chromosomal translocations affecting ETV1 or ETV4 are an underlying cause of carcinogenesis. Likewise, chromosomal rearrangements of the ETV1, ETV4 or ETV5 gene occur in prostate tumors and are thought to be one of the major driving forces in the genesis of prostate cancer. In addition, these three ETS proteins are implicated in melanomas, breast and other types of cancer. Complex posttranslational modifications govern the activity of PEA3 factors, which can promote cell proliferation, motility and invasion. Here, we review evidence for a role of ETV1, 4 and 5 as oncoproteins and describe modes of their action. Modulation of their activation or interaction with cofactors as well as inhibiting crucial target gene products may ultimately be exploited to treat various cancers that are dependent on the PEA3 group of ETS transcription factors.