The associations of alcohol consumption with risk of cardiovascular disease (CVD) and cancer have been extensively studied. Yet, the effect of moderate drinking on CVD and cancer remains unestablished, primarily because of opposing findings from conventional observational studies and Mendelian randomization (MR) studies. Specifically, conventional observational studies have found that light to moderate alcohol drinking is associated with a reduced risk of ischemic heart disease (1), ischemic stroke (2), and abdominal aortic aneurysm (3), but with an increased risk of breast cancer (4). In contrast, MR studies have shown that higher alcohol consumption, proxied by genetic variants related to alcohol metabolism and consumption (e.g., variants in the ADH1B gene) is associated with an increased risk of ischemic heart disease (5,6), stroke (5,7,8), atrial fibrillation (9), and abdominal aortic aneurysm (7). For other CVDs, including atrial fibrillation and hemorrhagic stroke, both conventional observational studies (2,10,11) and MR studies (7-9) have shown that moderate drinking increases the risk. With respect to cancer, MR findings of alcohol consumption in relation to cancer risk are inconclusive (12,13). As for alcohol, available evidence from observational and MR studies of coffee drinking and caffeine exposure in relation to health outcomes, particularly CVD and type 2 diabetes, is not conclusive (14-18). The reason for the disparate results is unclear. Given that alcohol and coffee are common exposures and the lack of consensus about the effects of light to moderate alcohol drinking on chronic diseases, further research is needed. Moreover, the molecular pathways whereby coffee and alcohol as well as specific alcoholic beverages may affect the risk of CVD, type 2 diabetes, and breast cancer have not been delineated. For example, the mediating role of circulating proteins (e.g., proteins modifying blood pressure and hormones), metabolites (e.g., lipids), and gut microbiome in the associations of alcohol and coffee and disease risk is unknown. The aim of this project is to decipher the influence of alcohol, coffee, and caffeine consumption on blood proteins, metabolites, gut microbiome, and major CVDs, type 2 diabetes, and breast cancer.