Since completion of the human genome sequence, considerable progress has been made in determining the genetic basis of human diseases. Understanding the genetic basis of coronary heart disease (CHD), the leading cause of mortality in developed countries, is a priority. Here we provide an update on the genetic basis of CHD, focusing mainly on the clinical manifestations rather than the risk factors, most of which are heritable and also influenced by genetic factors. The challenges faced when identifying clinically relevant genetic determinants of CHD include phenotypic and genetic heterogeneity, and gene-gene and gene-environment interactions. In addition, the etiologic spectrum includes common genetic variants with small effects, as well as rare genetic variants with large effects. Advances such as the cataloging of human genetic variation, new statistical approaches for analyzing massive amounts of genetic data, and the development of high-throughput single-nucleotide polymorphism genotyping platforms, will increase the likelihood of success in the search for genetic determinants of CHD. Such knowledge could refine cardiovascular risk stratification and facilitate the development of new therapies.