Abstract: The blood, vasculature, and nervous systems are among the complex tissues that arise through the exquisite ability to respond to oxygen gradients during development. In disease, the return of oxygen to oxygen-deprived (hypoxic) tissues following loss of blood flow adds a major complication to heart and lung surgeries. In a similar manner, cells pre-conditioned with hypoxia are better able to respond to more severe hypoxic conditions later on. However, different cell types are not equally sensitive to oxygen levels nor do they exhibit the same responses. At the pinnacle of the body’s oxygen control are endothelial cells (ECs), the cells that line vessels. These cells are drivers of physiological homeostasis and mediators of inflammation as well as responsible for new vessel formation and consequently, changes in oxygen levels throughout the entire body. However, the activities of ECs at different oxygen levels are poorly understood. Therefore, our goal is to understand the molecular changes of ECs under hypoxic stress. By using new genomic, statistical, and computational methods, we can discern key biochemical changes that may lead to new therapeutic understanding. We have generated insights from preliminary work with non-ECs that justify an in-depth genome-level characterization of EC hypoxic response.