Neoplasms progress to cancer through a process of natural selection. The rate of evolution, and thus progression is determined by three parameters: mutation rate, population size of the evolving neoplastic cells, and intensity of selection or rate of clonal expansion. All three parameters are reviewed in the context of Barrett's esophagus, a pre-malignant neoplasm. Although Barrett's esophagus is an ideal model for the study of neoplastic clonal evolution, similar studies may be carried out in a wide variety of human neoplasms. Evolutionary analyses provide insights for clinical management, including rates of progression to cancer and emergence of resistance to interventions.