ETS factors represent one of the largest families of transcriptional regulators and have known functional roles in many biological processes. Significantly, ETS factors have oncogenic and suppressive activity and their aberrant expression is associated with many of the processes that lead to prostate cancer progression. The targeting of transcription for therapeutic gain has met with some success. Therefore, better understanding the mechanisms that regulate ETS factor activity during both normal and aberrant transcription provides a novel means to identify processes that may be targeted in order to re-establish the normal ETS regulatory networks that are perturbed in cancer. Specific examples of altered ETS factor expression are highlighted, and therapeutic technologies that may be used to target ETS factors and their cofactors and downstream target genes in prostate cancer are discussed.