Soft tissue sarcomas comprise a group of exceedingly rare and histologically diverse malignancies. A multidisciplinary approach utilizing surgery, radiation therapy, and chemotherapy has evolved to address the challenge of effective treatment. Pertinent to this clinical goal are efforts to understand the molecular mechanisms underlying the etiology, proliferation, and metastatic phenotype of these tumors. This review describes the specific research efforts of our laboratory, which focus on the role of tumor suppressor genes and angiogenic factors as drivers of malignant behavior in soft-tissue sarcomas. By enlarging our knowledge of basic sarcoma tumor biology, it may be possible to identify important molecular mechanisms that can guide the design of future molecularly based therapies for this disease.