Cancer chemoprevention is defined as the pharmacologic intervention, by drugs or nutrient-components, with the process of carcinogenesis, in order to prevent the development of invasive malignant neoplasms. This preventive attempt is particularly challenging in cancer types, which have a long subclinical developmental phase, because of their low cellular proliferation rate and their slow pre-clinical evolution, until they become clinically detectable and therapeutically as well as prognostically relevant. Therefore, only certain specific cancer types are presently in the focus of clinical chemoprevention. Among the GI tract cancer, colorectal (CRC) as well as esophageal cancer have raised the most attention over the past decades, as they both share a long precancerous stage (the adenoma in CRC and Barrett's esophagus in the case of esophageal adenocarcinoma) which provides a window of opportunity to intervene and prevent development of cancer.In this review, we will focus on both CRC as well as esophageal adenocarcinoma (EAC).