The phenotypic progression to esophageal cancer is driven by an ongoing process of genomic instability constituting a number of clonal variants and leading to outgrowth of the "fittest" abnormal cell clones. Factors contributing to this process include exposure to chronic tissue damage, host susceptibilities, and alterations of molecular circuitries implicated in tissue homeostasis. Characterization of the host modifiers and molecular alterations will likely lead to the discovery of biomarkers useful for constructing stratified models defining cancer risk, allowing early detection, prediction of response to primary or secondary intervention, and prognostic evaluation of the disease. In addition, identification of key biologic pathways driving esophageal tumorigenesis will lead to development of new targeted interventions. The advent of increasingly sophisticated "omics" (ie, genomics, transcriptomics, proteomics, kinomics, pharmacogenomics), integration of systems biology, and expansion of biologic platforms bridging developmental physio-biology to cancer pathology constitute the backbone of novel tumor classifications and tailored therapies based on molecular signatures and profiles. Promising molecular targets, particularly those implicated in tissue homeostasis and stem cell maintenance, and their potential use in predictive models will be discussed.