Coronary heart disease (CHD) is a major cause of mortality in the Western world. CHD risk is known to be modified by both genetic and environmental factors. In this review, we look at the role of lipoprotein lipase (LPL) gene variants in predisposing to CHD risk and the important interaction between these genotypes and environmental factors (e.g. smoking). Gene-environmental interactions result in a greater than additive effect on risk and understanding these gene-environmental interactions has the potential not only for improving our understanding of the pathophysiology of the disease, but also in the development of new therapies and the targeting of specific therapies. For example, if a genotype increases risk in a particular environment, then those subjects would be encouraged to change their lifestyles more aggressively. Similarly at-risk subjects could be targeted with available therapies more appropriately.