The soft-tissue sarcomas are a diverse group of rare malignancies of mesenchymal tissue. Surgery is the principle modality of treatment but chemotherapy is used for the treatment of advanced or metastatic tumors. However, the response to chemotherapy is poor. Genetic factors are known to be important in the development of soft-tissue sarcomas and also have a role in response to treatment. This review discusses known genetic abnormalities in soft-tissue sarcomas. Molecular targets for treatment are also discussed along with a review of treatments that have been developed to date.