Cancer is a leading cause of death worldwide and within the US. While cancer initially arises from genetic mutations that transform otherwise healthy cells into cancerous cells, the growth, expansion, and metastasis of malignant tumors is dictated by local mechanical and biological cues, collectively known as the tumor microenvironment. Accordingly, to successfully treat cancer, one must target microenvironmental cues that emerge from tumor-associated stromal cells and extracellular matrix, in addition to the cancer cells. However, most cancer therapeutics do not effectively eradicate the disease, highlighting the need to improve our knowledge of cancer biology and develop novel treatments to target cancerous phenotypes with minimal side effects. Thus, the objectives of this dissertation are two-fold: to expand our current understanding of molecular mechanisms involved in tumor angiogenesis that contribute to cancer progression, and to create a human-based platform to screen anti-cancer therapeutics. During tumor progression, the cancer microenvironment evolves both chemically and mechanically. In line with the first goal above, endothelial cell behavior was investigated as a function of increased extracellular matrix stiffness and elevated vascular endothelial growth factor (VEGF) production, two known characteristics of the tumor microenvironment. My data indicate additive effects from both stimuli on VEGF receptor internalization, endothelial signaling, and proliferation, emphasizing the need to design cancer therapeutics to target multiple signaling pathways. While basic research such as that from goal number one can shed light on therapeutic targets, this basic science must subsequently be utilized in translational studies. Therefore, in line with the second goal, I designed a body-on-a-chip microfluidic device to investigate tumor-specific factors in cancer drug development. Such systems are critical in translating cancer biology research within drug screening models. My design creates a physiologically-relevant model to test both efficacy and toxicity of anti-cancer drugs, promoting unidirectional flow on a pumpless platform and using multicellular tumor spheroids as realistic tumor models. My data reveal both chemotherapeutic-induced cytotoxicity to the intended cancer cells and undesired toxic side effects in distant organs. Collectively, the data in this dissertation present a multifaceted approach to improve cancer treatment where basic science advances are translated to human-based drug screening systems.