Bone and soft tissue tumours are relatively rare and their classification is often found to be difficult by the pathologist. An accurate diagnosis is essential to predict biological behaviour and for therapeutic decision making. Over the last decades our knowledge on the genetic background of the different mesenchymal tumours has evolved, which has led to the 2002 WHO classification integrating pathology and genetics. Approximately 15-20% of bone- and soft tissue tumours has a specific translocation which can be used for diagnosis. The detection of specific translocations is not only important to confirm the diagnosis as was suggested by classical morphology and immunohistochemistry, but is especially useful in those cases with an unusual morphology, immunohistochemical profile or clinical presentation. Translocations can be demonstrated using RT-PCR on RNA isolated from frozen tumour tissue, or FISH on non-decalcified paraffin embedded material. In addition, a small subset of bone and soft tissue tumours is characterized by specific somatic gene mutations, e.g. KIT and PDGFRA mutations in gastrointestinal stromal tumours (GIST), and GNAS1 mutations in fibrous dysplasia and myxoma. Mutation analysis can be useful for diagnosis, and in case of GIST for predicting the response to the tyrosine kinase inhibitor Imatinib(Glivec).