Over the last scientific generation, observational epidemiology and clinical trials have revolutionized our understanding of causal risk factors predisposing to a variety of common diseases, perhaps most strikingly cardiovascular disease. Pretty much every member of the public now knows that smoking, high blood pressure, high levels of blood cholesterol, and diabetes predispose to the development of coronary heart disease (CHD), and yet one does not have to venture too far back into last century to find a time when all of this was completely unknown. The extraordinary power of large blood-based observational epidemiological studies to identify associations between risk factors and complex diseases has been one of medical science's great recent success stories. No less important have been the data from clinical trials confirming that associations that have been found in observational studies are causal—by showing that treatment of particular risk factors using suitably specific therapeutic agents diminishes the risks of developing disease. The third important strand of evidence confirming (albeit indirectly) causality of a risk factor consists of studies in animal models of disease; the technology to create transgenic and gene-targeted animals has resulted in an explosion of activity in this field. Although such models often confirm the importance of risk factors in humans (for example, the development of stroke in certain hypertensive rat models, or of atheromatous disease in genetically engineered hyperlipidaemic mice), importantly they do not in all cases.