Elevated plasma cholesterol is a heritable trait and a risk factor for the development of cardiovascular disease. Although several major biochemical pathways regulating cholesterol metabolism have been identified, questions regarding the details of this regulation remain. In fact, common genetic polymorphisms in candidate genes explain only 5 to 7% of variation in high- and low-density lipoprotein cholesterol levels between individuals. This suggests that many of the factors influencing cholesterol metabolism, and potentially the etiology of cardiovascular disease, are unknown. Here, we review recent functional genomic research that, combined with results from genome-wide association studies, provides a powerful tool to identify novel candidate genes relevant to cholesterol metabolism.