Soft tissue sarcoma is an extremely rare malignant disease that includes more than 15 distinct histologic subtypes. While all share a propensity for metastasis to the lungs, the clinical presentation and pattern of spread for the specific subtypes are remarkably viable. Little is known about the etiology of soft tissue sarcoma other than several well described epidemiological associations between ionizing and other toxic agents and several of the soft tissue sarcoma histologic subtypes. The key to understanding the etiologic factors driving soft tissue sarcoma proliferation and dissemination lies in understanding the molecular mechanisms underlying these oncologic processes. Progress in this regard has been difficult because of the rarity of this disease. This report reviews the current state of knowledge for three of the most important considerations involving the molecular etiology of soft tissue sarcoma: growth factors and their receptors, nuclear and cytoplasmic oncogenes, and tumor suppressor genes. As we learn more about these molecular mechanisms leading to proliferation and dissemination of soft tissue sarcoma, molecularly based genetic therapies will become a reality for this all too devastating, albeit rare, disease.