In spite of a significant improvement in the control of numerous predisposing risk factors, cardiovascular disease (CVD) remains a major health problem and a common cause of death and disability in our Western societies. A genetic predisposition to CVD has been documented in both animal models and in humans. However, a precise definition of the genetic factors responsible for common forms of CVD is still lacking, mainly because of its complex nature, the confounding presence of other predisposing risk factors, and the genetic heterogeneity of human populations.Linkage studies in experimental crossbred rats and candidate gene testing in human populations represent two of the most widely used approaches for the analysis of the genetic basis of common forms of CVD. On the one hand, the use of animal models has highlighted several potential candidates, whereas controversial findings have been provided by the enormous amount of polymorphisms/association studies.The recent introduction of intermediate disease phenotypes has led to a reductionist approach that may significantly contribute to achieve the discovery of important information on the genetics of CVD.