OBJECTIVE Epidemiological studies consistently link moderate alcohol use with a lower risk of cardiovascular disease, but a number of important issues remain controversial. These include the putative impact of non-alcoholic constituents of some alcoholic beverages, the role of genetic factors, potential mechanisms for this association, and confirmation of the relationship in experimental models. RESULTS Although high-density lipoprotein cholesterol (HDL-C) is considered the primary mediator of the cardiovascular effects of moderate drinking, recent evidence has shown the alcohol-HDL-C relation is not linear beyond the range of moderate drinking. Moderate alcohol use also has important inverse relations with inflammatory factors. Some, but not all, animal models confirm the anti-atherogenic effects of ethanol and highlight inflammatory factors as one possible mechanism. The non-alcoholic constituents of red wine also have anti-atherogenic and perhaps even life-extending properties in vitro, but their relevance to humans remains uncertain. Genetic variants of the apolipoprotein E and interleukin 6 genes in humans may modify how alcohol influences atherosclerosis, further emphasizing the importance of HDL-C and inflammatory factors as mediators. CONCLUSIONS The robust relationship between moderate drinking and lower risk of cardiovascular disease remains an intriguing area of investigation. Clarifying potential gene-environment interactions and translational research into uses for non-alcoholic components will be important areas for future investigation.