Atherosclerosis and the acute coronary syndromes (ACS) are very prevalent in the developed world, and they are on the increase. These complex diseases result from interplay between genes, lifestyle, and environment. Lifestyle and environmental factors are now largely known, and research efforts are shifting towards the discovery of predisposing genetic factors. Several approaches are being undertaken including family studies, genetic association studies, and studies in mice. Guided by our increasingly detailed understanding of the processes underlying cardiovascular disease many candidate genes have been evaluated including those encoding adhesion molecules, chemokines and cytokines, and matrix metalloproteinases. Genetic association studies using polymorphisms in these genes have often given conflicting results that are difficult to judge. The literature on this work will be reviewed here and some common themes emerge. These include the complexities surrounding polymorphisms found within a cluster of genes of related function, the possibility that an underlying condition that predisposes to endothelial dysfunction is required for certain polymorphisms to exert their effect, the possibility that a gene, or another gene tightly linked to it, modifies risk for a traditional risk factor for atherosclerosis or its acute effects, and the notion that studying combinations of genotypes, or combinations of genotypes and predisposing traditional factors may be a better reflection of the situation in vivo. The practical difficulties of elucidating such complex influences are also discussed.