The search for common genetic determinants of plasma lipoproteins began in the early 1980s. Despite some exceptions, these efforts have not yet yielded a set of biological markers that can be used in clinical practice. By contrast, successes in defining the molecular basis of rare single-gene disorders, such as familial hypoalphalipoproteinemia, have shown the value of experimental designs that focus on genomic analysis of individuals within the tails of Gaussian distributions of quantitative lipoprotein traits. For example, this strategy showed that a small but relevant proportion of individuals within the <5% tail of plasma HDL-cholesterol distribution have mutations in genes that cause familial hypoalphalipoproteinemia. The value of clinical testing for genomic variants as an adjunct to a biochemical measurement of plasma lipoproteins, however, is at best questionable. A more direct impact of genetic studies is that definitions of 'common' and 'large genetic effects' have become more tempered, reflecting perhaps the biological reality that plasma lipoproteins are probably determined by the aggregate of numerous modest and occasional large genetic effects in addition to environmental factors. Here, we review recent progress on genomic variants and cholesterol metabolism, and discuss the impact these genetic studies will have on clinical cardiology.