Peripheral arterial disease (PAD) is a major health problem in which arteries within the systemic vasculature become partially or fully blocked, often due to atherosclerosis, leading to a significant reduction in blood flow to tissue. Patients often require surgical bypass grafts to restore flow to their tissue; in extreme cases, amputation is required. The absence of data regarding the relative importance of adaptations in collateral arteries, arterioles, and capillaries to compensation after arterial occlusion is a major roadblock for the development of successful and noninvasive therapies for PAD patients. The objective of this project is to integrate experimental and theoretical techniques to assess the significance of changes in vascular segments at rest and during exercise subsequent to a major arterial occlusion on an acute and chronic time frame. Model-predicted values of vascular resistance are compared with experimental studies to validate the model. The model is extended to predict changes in vessel diameter according to mechanistic responses to pressure, shear stress, and metabolism following an occlusion. Theoretical results suggest that therapies that increase collateral diameter in combination with distal microcirculation adaptations provide the maximum benefit to patients with PAD. Ultimately this project offers a first step in optimizing experimental design and diagnostic criteria to focus on the most relevant vascular segments in studies of vascular compensation in health and disease.