The genetic basis of coronary artery disease (CAD) is complex, and the fact that an alarmingly high proportion of reported associations between genetic variants and CAD are not replicated has generated uncertainty as to whether molecular genetics is ever going to deliver on the promises delivered in the late 1990s. However, during 2007, the first generation of large-scale genome-wide association studies using high-density, single nucleotide polymorphism genotyping arrays have revealed genetic variants that are robustly associated with CAD and CAD-related traits such as type 2 diabetes and obesity. In particular, a robust susceptibility locus for CAD has been identified on chromosome 9p21. Also, evidence has been obtained that multiple rare alleles with fairly strong phenotypic effects may contribute to the genetic heritability of CAD, in addition to common variants with a modest impact on risk. Furthermore, new mechanistic connections have been discovered between different common complex diseases including CAD. This review focuses on the challenges and recent advances of molecular genetics in dissecting the molecular pathophysiology of atherothrombosis and defining novel targets for treatment.