The precise molecular mechanisrms that lead to coronary artery disease (CAD) and myocardial infarction (MI) are not understood, despite a wealth of knowledge on predisposing risk factors and pathomechanisms. CAD and MI are complex genetic diseases; neither the environment alone nor a single gene cause disease, but a mix of environmental and genetic factors lead to atherosclerosis of the coronary arteries and subsequent manifestation of clinical disease. The biological complexity of atherosclerotic disease results from unknown or unpredictable interactions of many genetic and environmental factors which, by themselves, have only been partially identified. According to current knowledge, genetic variations in causative or susceptihility genes form the basis of molecular mechanisms that, together with environmental impact, lead to CAD/MI and determine its clinical course. Linkage analysis, which follows 'disease' alleles in families, or genetic association in a population of unrelated individuals are tools used in the search for chromosomal loci and candidate genes that are involved in these complex diseases. Progress in sequencing and mapping of the human genorne and efforts to identify all of the expected one million single nucleotide polymorphisms (SNPs) expected to be present in mankind will allow new approaches such as genome-wide association studies. The contribution of the current state of knowledge on genetic variation in man towards the dissection of CAD/MI as complex traits is sobering. Raised expectations with regard to the power of molecular genetic studies as compared to the traditional pathophysiological experimental approaches, lack of precise clinical phenotyping, lack of functional characterisation of gene variants, and the vast number of yet undetected genes may provide some explanation. Except for certain polymorphisms in lipid genes (i.e., apolipoprotein E [apo E]) or rare genetic variations (i.e., LDL receptor), which have a causal effect on both the intermediate (LDL-cholesterol level in plasma) and the clinical phenotypes (CAD/MI), the role of most gene polymorphisms is controversial or unknown. Despite the enormous progress in sequencing the human genome and in molecular genetic and bioinformatic techniques during the past decade, the progress in mapping and identifying genes responsible for complex traits such as CAD/MI has been modest and presents a formidable challenge to medical research in the 21st century.