Soft tissue sarcomas are a heterogeneous group of malignant mesenchymal tumors, and novel tumors biomarkers and therapeutic targets are required to achieve early diagnosis and optimize therapy for individual patients. Global protein expression studies, an approach known as "proteomics", can offer important clues for understanding tumor biology that cannot be obtained by other approaches. Proteomic studies, such as two-dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry, have provided protein expression profiles of soft tissue tumors that can be used to develop novel diagnostic and therapeutic biomarkers and allow molecular classification of tumors. In this article, a brief description of the methodology will be provided, followed by a few examples of the recent proteomic studies that have generated new information for the diagnosis, classification and treatment of soft tissue tumors.