Chromosomal rearrangements play a causal role in haematological and mesenchymal malignancies. Importantly, the resulting gene fusions can serve as specific therapeutic targets, as exemplified by the development of imatinib (Gleevec), which specifically inhibits the BCR-ABL gene fusion product that defines chronic myeloid leukaemia. Recently, gene fusions involving the prostate-specific gene transmembrane protease, serine 2 (TMPRSS2) and members of the erythroblastosis virus E26 transforming sequence (ETS) family of transcription factors were identified in most of PSA-screened prostate cancers. In this review, we summarize the identification, characterization and detection of TMPRSS2:ETS gene fusions and their role in prostate cancer development. We also discuss the discovery of additional 5' partners that define distinct classes of ETS gene fusions based on the prostate specificity and androgen responsiveness of the 5' partner. Additionally, we also summarize conflicting reports about associations between gene fusion status and patient outcome. The specificity of ETS gene fusions in prostate cancer suggests that they may have causal roles in prostate cancer and suggest utility in prostate cancer detection, stratification and treatment.