Coronary heart disease is the leading cause of death in developed countries. This alarming statistic is partly attributable to lifestyle, and partly due to the genetic factors that make humans highly susceptible to atherosclerotic vascular disease. The principal metabolic causes of atherosclerosis include hyperlipidemia, hypertension, obesity, insulin resistance and diabetes mellitus. Here we discuss the aetiology of familial combined hyperlipidemia (FCHL), a highly atherogenic disorder affecting 1-2% of the Western world. Genome-wide linkage studies indicate that more than three genes contribute to the pernicious lipid profile of FCHL, and that these genes reside within the 1q21-23, 11p14.1-q12.1 and 16q22-24.1 chromosomal regions. Other loci include 1p31, 6q16.1-16.3 and 8p23.3-22, but the linkage data for these are not yet persuasive. Combined linkage and association analyses provide compelling evidence for the involvement of two distinct alleles at the APOA1/C3/A4/A5 gene cluster in the transmission of FCHL. An important lesson arising from the study of a complex genetic disorder, such as FCHL, that lacks a consensus on diagnostic criteria, is that an understanding of complex genetic disorders can derive from comparative analyses of genome-wide linkage data generated from conditions that share phenotypic overlap. The identification of potential genetic overlap between FCHL and the Metabolic Syndrome, which is estimated to affect 47 million Americans, promises to deliver new targets for reducing the risk of important conditions such as cardiovascular disease and stroke.