Translocations affecting USP6 have been initially found in primary aneurysmal bone cysts (ABC), a benign, but locally aggressive bone lesion that occurs predominantly during the first two decades of life. USP6 rearrangements are restricted to spindle cells in primary ABC, indistinguishable from surrounding normal spindle cells. The resulting fusion genes detected are formed by juxtaposition of the USP6 coding sequences to the highly active promoter sequences of several partner genes, as e.g. CDH11, COL1A1, OMD, TRAP150, and ZNF9, leading to the transcriptional upregulation of USP6. No true fusion genes are formed. More recently, nodular fasciitis (NF), another mesenchymal lesion, has been tested positive for USP6 rearrangements. NF is a subcutaneous pseudosarcomatous myofibroblastic proliferation of unknown pathogenesis that regresses spontaneously when not surgically resected. The translocation results in the fusion of the promoter region of MYH9 located on 22q12.3 to the entire coding sequence of USP6 and subsequently in upregulated USP6 expression. For both lesions it is assumed that the detection of USP6 rearrangements by Fluorescence in situ Hybridization might represent a valuable diagnostic tool.