It is generally considered that the genetics of atherosclerosis and its complications involves a large number of genes with common alleles having weak effects on disease risk but possibly interacting with each other and with non-genetic factors. In such a complex system, absence of marginal effects (effects of polymorphisms considered one at a time) is insufficient to exclude the implication of a polymorphism on disease risk. Investigating polymorphisms and even genes one by one is no longer appropriate. It is necessary to focus on biological systems and integrate the contribution of genetic as well as non-genetic factors and their interactions. Hopefully, system genetics will ultimately improve our understanding of the genetic architecture of complex traits.