Regular moderate wine consumption is often associated with reduced morbidity and mortality from to a variety of chronic diseases in which inflammation is a root cause. Wine comes in a wide variety of styles that contain quite different ethanol and polyphenol contents. Controversy remains as to whether the alcohol or polyphenols contribute more to the health benefits of regular moderate wine consumption. The variety of wines available to consumers can be expected to affect health differently in accordance with a particular wine's total polyphenolic content and spectrum of individual polyphenols. The overall effect of wine consumption on health depends upon the total amounts consumed, the style and possibly the pattern of consumption. The apparent effect of wine consumption may be modified by the non-wine diet composition of the consumer in that alcohol may appear as the primary component in consumers with high fruit, vegetable and whole grain intakes while phytochemical benefit may become significant in diets where wine is the primary dietary source of phytochemical. In this review, wine polyphenol mechanisms of action will be reviewed in connection with the mechanism the development of atherosclerotic cardiovascular disease (ASCVD). Selected clinical studies published in 2004-2008 were reviewed. Experimental requirements for valid clinical studies, translation of in vitro to in vivo application and areas where additional evidence needs to be developed were identified.