The RCT with pre-specified end points is considered the best path to scientific truth in medical matters. Randomization is the best method of controlling for known and unknown confounders. Blinding, often part of the process, minimizes bias. The logistics of RCTs are more difficult for study of lifestyle changes than for pharmacologic or procedural interventions. We have no RCTs of moderate alcohol drinking with CAD or other fatal event end points. For ethical reasons the effects of heavy drinking are not amenable to an RCT, but the wish for such studies of chronic disease effects of moderate drinking is often expressed. Generally there has been little discussion of practical considerations. The hypothesized fractional benefits would require large numbers in a costly multicenter trial of long duration. Even assuming such an effort, could a representative study group, after exclusions, be recruited? If an appropriate population was acquired, could compliance with randomization to daily/almost daily moderate drinking or none be maintained for years? Is blinding possible? What alcohol dose(s) should be used? How many arms are needed (e.g., beer, liquor, white wine, red wine, alcohol-water mixture, placebo)? These are formidable problems. We do have studies relevant to intermediate “surrogate” markers, such as high-density lipoprotein cholesterol, antithrombotic effects, and endothelial function. There is also promise in “natural' experimental randomization by metabolic genetic polymorphisms related to alcohol metabolism. Unfortunately, it is likely that we will be left much-dependent upon observational epidemiology.