Recurrent gene fusions between the androgen-regulated genes TMPRSS2 and the ETS transcription family members ERG, ETV1, and ETV4 have been implicated in the majority of clinically localized prostate cancers. To determine if these fusions are also present in androgen-independent metastatic prostate cancer, a previously validated fluorescent in situ hybridization (FISH) split probe strategy was used to analyze the frequency and mechanism of these gene fusions in samples isolated from 30 prostate cancer patients. The results indicate that the high frequency of TMPRSS2-ETS rearrangements is maintained during progression to an androgen-independent state. The most common gene fusion, TMPRSS2-ERG, was associated with interstitial deletion (Edel) in 39% to 60% of clinically localized disease and in all of the androgen-independent metastatic prostate sites. Furthermore, multiple sites from an individual case harbored the same gene fusion molecular subtype suggesting clonal expansion of disease. These findings suggest that TMPRSSE-ERG with Edel is an aggressive and, in this study, uniformly lethal molecular subtype of prostate cancer associated with androgen-independent disease. For details, see the article by Mehra et al. on page 3584 of this issue.