Current chemotherapeutic agents are potent enough to kill cancer cells. Nonetheless, failure of chemotherapies for many cancers (e.g. breast and pancreatic cancers and various sarcomas) is primarily because these agents cannot reach cancer cells in amounts sufficient to cause complete cure. The abnormal microenvironment of these tumors drastically reduces perfusion and results in insufficient delivery of therapeutic agents. Tumor structural abnormalities is in large part an effect of mechanical stresses developed within the tumor due to unchecked cancer cell proliferation that strains the tumor microenvironment. Alleviation of these stresses has the potential to normalize the tumor, enhance delivery of drugs and improve treatment efficacy. Here, I propose to test the hypothesis that re-engineering the tumor microenvironment with stress-alleviating drugs has the potential to enhance chemotherapy. To explore this hypothesis, I will make use of a mixture of cutting-edge computational and experimental techniques. I will develop sophisticated models for the biomechanical response of tumors to analyze how stresses are generated and transmitted during tumor progression. Subsequently, I will perform animal studies to validate model predictions and indentify the drug that more effectively alleviates stress levels, normalizes the tumor microenvironment and improves chemotherapy. Successful completion of this research will reveal the mechanisms for stress generation and storage in tumors and will lead to new strategies for the use of chemotherapy.