Whether examined at the micro- or macroscale, biological phenomenona are not exempt from physical laws and principles. The vasculature is frequently utilized as a model system to better understand and analyze the consequences of biophysical forces on biochemical processes and ultimate biological phenotypes. Given the complexities of biological systems, there is an inherent need to focus in order to properly elucidate mechanisms. Mechanotransduction and cell mechanics in various stages of angiogenesis have long been examined at distinct length-scales ranging from subcellular, cellular, multi-cellular, tissue, and beyond. This chapter will highlight research over the past decades that have contributed to revealing the importance and interplay between biophysical forces (compressive and shear flow) and biological behavior (motility, regulation of smooth muscle cells, polarity). Abnormal biophysical forces, such as hypertension, contribute significantly to vascular diseases, including atherosclerosis and aneurysm formation. Understanding the relationship between biophysical forces and biological behavior is required to understand the mechanisms of vascular disease.