ERG (ETS transcription factor ERG) rearrangements have been observed in 40-60% of prostate cancers identified via prostate-specific antigen (PSA) screening. The most common aberration affecting ERG is the interstitial deletion of about 3 Mb at the chromosomal region 21q22 found in 90% of the cases. This deletion leads to the fusion of the hormonally regulated promoter of the TMPRSS2 (transmembrane serine protease 2) gene to the coding region of ERG, resulting in overexpression of the ERG transcription factor. However, about 10% of the ERG rearranged prostate cancer cases show alternative fusions, as e.g. SLC45A3-ERG or NDRG1-ERG. Several studies detected associations of ERG rearrangements with histomorphologic features as well as characteristic chromosomal copy number changes and gene expression signatures, defining a distinct sub-class of prostate cancers with unfavorable prognosis. Hence, the evaluation of the ERG rearrangement status in tissue or urine samples by FISH might be of diagnostic and prognostic relevance. EWSR1-ERG gene fusions present in about 10% of patients with Ewing sarcoma may result from complex genomic rearrangements and may therefore not be detected by FISH analysis or may result in a non-classical translocation signal pattern.