The development of Barrett's esophagus (BE), which is specialized intestinal metaplasia in the lower esophagus, is considered an important first step in the development of esophageal adenocarcinoma (EAC). In this talk I will introduce a mathematical framework that enables the development of a biologically-based cancer model to describe the stepwise progression from normal esophageal tissue to BE metaplasia to dysplasia to cancer. We recently demonstrated (Curtius et al., 2015, PLoS CompBio) the consistency of this model with EAC incidence data over the past 4 decades in the US population and also broadly with prevalence data on dysplastic precursors in the population. Moreover, our framework seamlessly integrates relevant cell-level processes during cancer development with a spatial screening process to provide a clinically relevant model for detecting (pre)malignant clones within the BE tissue. The model thus enables a quantitative evaluation of the clinical efficacy and sensitivity of current screening protocols to detect neoplasia (dysplasia and preclinical cancer) in the esophageal lining.  Finally, I will describe the analysis of molecular clock data to estimate the time when BE first arose in a patient. This information is critical in assessing the patient’s risk of developing EAC.