Tobacco smoking remains the second largest preventable cause of mortality and morbidity worldwide. Exposure to tobacco smoke causes coronary disease, atherosclerosis and ischemic vessel disease. The degree of this risk is proportional to the amount of smoking and it varies from individual to individual because of between-individual differences in genetic background. While the chemical properties of tobacco smoke are relatively well characterized, the mechanisms by which smoking leads to disease and the genetic factors that determine susceptibility to these diseases are not well understood. The purpose of the present review is to describe the interaction between DNA variants in some important genes and cardiovascular diseases; and how the exposure to cigarette smoke significantly modifies the association between genetic variants and cardiovascular risk. A great number of gene-enzymes that usually protect against cardiovascular events may be adversely influenced by tobacco smoke and, through this way, exert less effective action.