Prostate cancer is unique among carcinomas in that a fusion gene created by a chromosomal rearrangement is a common driver of the disease. The TMPRSS2/ERG rearrangement drives aberrant expression of the ETS family transcription factor ERG in 50% of prostate tumors. Similar rearrangements promote aberrant expression of the ETS family transcription factors ETV1 and ETV4 in another 10% of cases. Together, these three ETS factors are thought to promote tumorigenesis in the majority of prostate cancers. A goal of precision medicine is to be able to apply targeted therapeutics that are specific to disease subtypes. ETS gene rearrangement positive tumors represent the largest molecular subtype of prostate cancer, but to date there is no treatment specific to this marker. In this chapter we will review the latest findings regarding the molecular mechanisms of ETS factor function in the prostate. These molecular details may provide a path towards new therapeutic targets for this subtype of prostate cancer. Further, we will describe efforts to target the oncogenic functions of ETS family transcription factors directly as well as indirectly.