Hypoxia is a naturally occurring phenomenon in coastal waters that is increasing in frequency and extent due to human activities. There is a pressing need to understand how organisms will be able to respond and adapt to future oxygen limitation. The eastern oyster, Crassostrea virginica, is an ecologically important bivalve that is threatened by the increasing incidence of low oxygen events. Little is known about the capacity of C. virginica to cope with projected deoxygenation or the potential ecological implications of reduced oxygen availability. The primary objectives of this dissertation research were to 1) characterize the intraspecific variability in physiological and molecular responses to hypoxia for oysters from the Chesapeake Bay and 2) develop a model to predict the implications of hypoxia on oyster population ecology. In Chapter 2 I assessed the survival and heart rate responses under low oxygen stress for oysters sourced from reefs experiencing varying frequencies of hypoxia exposure. Results indicated that prior hypoxia exposure does not confer increased survival under low oxygen stress but may relate to sublethal physiological differences in tolerance, particularly for oysters with a greater frequency of prior hypoxia exposure. In Chapter 3, I used four different analytical approaches, principal components, differential gene expression, co-expression gene network, and transcriptional frontloading analyses, to assess intraspecific differences in oyster transcriptomic response to hypoxia. No statistically significant differences in gene expression response between sites were observed indicating that prior hypoxia exposure may not have affected the regulation of expression under hypoxic stress. However, while not statistically significant, gene expression patterns suggested transcriptional frontloading as a possible mechanism of increased hypoxia tolerance in oysters. Finally, in Chapter 4, I developed a Dynamic Energy Budget model integrating dissolved oxygen concentration as a forcing variable to make predictions about oyster growth and reproduction under varying oxygen conditions. Model outputs indicated that low oxygen exposure reduces oyster growth, fecundity, and spawning frequency. Collectively, this dissertation research affirms that low oxygen availability negatively affects oyster physiology and ecology, and emphasizes the importance of continued research into the capacity of oysters to tolerate future increases in coastal hypoxia.