The tumor extracellular matrix (ECM) plays an important role in facilitating tumor growth and mediating tumor cells' resistance to drugs. However, during drug development, potential chemotherapeutics are screened in plastic plates, which lack relevant ECM physicochemical cues. In order to improve drug development process, this dissertation includes the development of relevant 2D and 3D biomaterial systems that can be used to study carcinoma cell response to drug treatment. A novel poly(ethylene glycol)-phosphorylcholine (PEG-PC) high-throughput biomaterial platform was developed to study how the ECM mechanochemical properties affect cancer cells' response to drug. The PEG-PC biomaterial is optically transparent, has a mechanical range from 1 to 10,000 kPa in Young's modulus, and allows easy coupling of cell adhesive proteins. When testing several breast and liver cancer cell lines on PEG-PC gels that had different stiffnesses and integrin-binding sites, there was a significant increase in drug resistance with increasing substrate stiffness. It was found that this stiffness-induced drug resistance was independent of Rho-ROCK and EGFR signaling, but co-administration of a β1 integrin antibody, or an inhibitor to JNK, with sorafenib effectively eliminated the stiffness-mediated sorafenib resistance. Finally, 3D hydrogel systems, poly(N-isopropylacrylamide)-PEG (PNIPAAm-PEG) and PEG-Maleimide, were utilized to create multi-cellular spheroids to study drug resistance in 3D. Both SkBr3s and MDA-MB-231s were tested with sorafenib, lapatinib, temsirolimus, and doxorubicin across varying moduli and geometry (plastic, 2D and 3D hydrogels, spheroid) in different medium conditions. For some drugs, the change in platform or medium was found to have the largest effect on the variation of the IC-50 than the change in modulus. Specifically, the IC-50s varied the most when SkBr3s were treated with sorafenib and temsirolimus and when MDA-MB-231s were treated with sorafenib and lapatinib. However, when treated with doxrorubicin, the IC-50s of both cell types were similar across all platforms. These results demonstrate the utility of tailored biomaterial systems to address basic questions related to tumor microenvironment and drug resistance in cancer, and highlight the importance of incorporating relevant ECM factors into drug testing.