The risk for coronary artery disease (CAD) is inversely correlated with high-density lipoprotein (HDL) cholesterol plasma levels. These plasma HDL cholesterol levels are influenced by the activity of a number of enzymes and receptors, and therefore, variations in the genes encoding for these proteins may consequently result in an altered CAD risk. Identification of such pivotal players in HDL cholesterol metabolism that are also strongly associated with CAD risk is crucial for the materialization of novel therapeutic modalities. A large amount of knowledge has been obtained by studies involving families with extreme HDL phenotypes specific to molecular defects. In fact, thus far, monogenetic defects have been described in the genes coding for apolipoprotein A-I, adenosine triphosphate-binding cassette transporter A1, cholesterol ester transfer protein, the lack of endothelial lipase (LIPG), phospholipid transfer protein, and lecithin-cholesterol acyltransferase. Despite the fact that the total number of carriers of such mutations is rather small, much can be gained by extensively studying the metabolic and vascular consequences of these mutations. Surrogate markers for atherosclerosis have proved to be useful to overcome this sample size limitation and have been widely exploited to study families with decreased or increased HDL cholesterol levels in order to correlate HDL cholesterol phenotypes to atherosclerotic burden in cases and controls. Apart from such extreme phenotype approaches, novel population-based genome-wide association studies have been used to decipher the link between genetic loci and HDL cholesterol levels, and the identification of novel HDL cholesterol-related genes is eagerly awaited. These might be instrumental in the ongoing fight against atherosclerosis.