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Esophageal adenocarcinoma (EAC) is a lethal cancer requiring improved screening strategies and treatment options due to poor detection methods, aggressive progression, and therapeutic resistance. Emerging circulating tumor DNA (ctDNA) technologies may offer a unique non-invasive strategy to better characterize the highly heterogeneous cancer and more clearly establish the genetic modulations leading to disease progression. The presented review describes the potential advantages of ctDNA methodologies as compared to current clinical strategies to improve clinical detection, enhance disease surveillance, evaluate prognosis, and personalize treatment. Specifically, we describe the ctDNA-targetable genetic markers of prognostic significance to stratify patients into risk of progression from benign to malignant disease and potentially offer cost-effective screening of established cancer. We also describe the application of ctDNA to more effectively characterize the heterogeneity and particular mutagenic resistance mechanisms in real-time to improve prognosis and therapeutic monitoring strategies. Lastly, we discuss the inconsistent clinical responses to currently approved therapies for EAC and the role of ctDNA to explore the dynamic regulation of novel targeted and immunotherapies to personalize therapy and improve patient outcomes. Although there are clear limitations of ctDNA technologies for immediate clinical deployment, this review presents the prospective role of such applications to potentially overcome many of the notable hurdles to treating EAC patients. A deeper understanding of complex EAC tumor biology may result in the progress toward improved clinical outcomes.