It is a matter of common knowledge that incidence rates of inflammatory and neoplastic conditions of the distal oesophagus, such as eosinophilic oesophagitis, Barrett´s oesophagus, oesophageal adenocarcinoma (OAC), and their common main risk factor gastro-oesophageal reflux disease (GORD) are on the rise. All conditions were linked to lifestyle-related risk factors such as diet or medication without a comprehensive understanding of the pathophysiological mechanisms involved. It is a very recent knowledge that the oesophagus harbours a specific and unique microbiome that changes in correlation with disease conditions. Recent epidemiological data indicate potential causative relationships between disease-specific risk factors, changes in the gastrointestinal microbiota composition, and disease progression, as already reported in other gastrointestinal diseases such as colorectal cancer. It is plausible that alterations in the microbial community might account for inflammatory or potential carcinogenic changes in the microenvironment via interference with the immune system, bacterial defence, and metabolic pathways. It is of crucial importance to accomplish a more comprehensive and systemic understanding of the complex mechanistic interactions between host, lifestyle, environment, and microbiota to elucidate the onset, progress, and potential therapy of oesophageal diseases, as well and their association with other diseases of the gastrointestinal tract.