Excessive alcohol consumption and heavy smoking are the main risk factors of upper digestive tract cancer in industrialized countries. The association between heavy drinking and cancer appears to he particularly prominent in Asian individuals who have an inherited deficient ability to detoxify the first metabolite of ethanol oxidation, acetaldehyde. Alcohol itself is not carcinogenic. However, according to cell culture and animal experiments acetaldehyde is highly toxic, mutagenic, and carcinogenic. In addition to somatic cells, microbes representing normal human gut flora are also able to produce acetaldehyde from ethanol. After the ingestion of alcoholic beverages, this results in high local acetaldehyde concentrations in the saliva, gastric juice, and the contents of the large intestine. In addition, microbes may produce acetaldehyde endogenously without alcohol administration. This review summarizes the epidemiological, genetic, and biochemical evidence supporting the role of locally produced acetaldehyde in the pathogenesis of digestive tract cancer. Special emphasis is given to those factors that regulate local acetaldehyde concentration in the contents of the gastrointestinal tract. The new evidence presented in this review may open a microbiological approach to the pathogenesis of digestive tract cancer and may have an influence on future preventive strategies.