Soft tissue sarcomas are relatively rare tumors that are generally treated with a multimodality approach including surgery, chemotherapy, and radiation therapy. Despite this aggressive tri-modality therapy, greater than 50% of soft tissue tumors will recur and result in diffuse metastatic spread of disease and ultimately death of the patient. It is this clinical scenario that drives the development of preclinical experimental studies designed to explore alternative treatments or enhance the effectiveness of existing therapies. Rapid developments in the field of molecular biology have led to the understanding of basic cellular processes governed by oncogenes and tumor suppressor genes. These cellular genes are sometimes overexpressed, mutated or even deleted from tumor cells. Cytogenetic analysis has led to the discovery of sarcoma fusion genes which encode for oncoproteins peculiar to specific subtypes of soft tissue sarcomas. These fusion genes have proved to be helpful in terms of diagnostic dilemmas and are now being used as targets in treatment strategies aimed at suppression of the cellular expression and action of these oncoproteins. Tumor suppressor genes such as p53 and the retinoblastoma tumor suppressor play important roles in growth inhibition and cell cycle progression. These tumor suppressors are often mutated or deleted in soft tissue sarcomas. Using gene therapy strategies, p53 can be reintroduced into sarcoma cells and has been shown to result in a dramatic decrease in cell survival. It also appears that p53 may sensitize these tumor cells to radiation and chemotherapy agents. Strategies which can drive tumor cells into programmed cell death pathways are also showing promise as novel treatment approaches to soft tissue sarcomas. This review will highlight some of the current research exploring novel treatment strategies aimed at molecular targets. Further development of these and other preclinical experimental programs are important in improving the outcome for patients with these rare soft tissue tumors.