Inheritance plays an important role in the pathogenesis of coronary artery disease (CAD) and myocardial infarction (MI). Yet, for decades, gene discovery proved to be difficult, as variants in candidate genes failed to show robust association with the disease. However, the advent of genome-wide association studies allowed the identification of multiple genetic loci associated with risk of CAD/MI. The discoveries revealed several unexpected findings. First, the strongest association with CAD/MI in the genome was located to chromosome 9p21. 3, with poor annotation of genes. Even more surprisingly, of the multiple regions identified for CAD/MI risk, only a few relate to traditional risk factors such as low-density lipoprotein cholesterol. Moreover, all currently identified loci confer a rather modest risk increase, with a risk per allele of about 10-25%. Together, these surprising findings brought about by genome-wide association studies suggest significant gaps in the traditional understanding of the pathophysiology of CAD/MI.