Recent genome-wide association studies have identified numerous common genetic variants associated with plasma lipid traits and have provided new insights into the regulation of lipoprotein metabolism including the identification of novel biological processes. These findings add to a body of existing data on dietary and environmental factors affecting plasma lipids. Here we explore how interactions between genetic risk factors and other phenotypes may explain some of the missing heritability of plasma lipid traits.Recent studies have identified true statistical interaction between several environmental and genetic risk factors and their effects on plasma lipid fractions. These include interactions between behaviors such as smoking or exercise as well as specific dietary nutrients and the effect size of specific genetic variants on plasma lipid traits risk and modifying effects of measures of adiposity on the cumulative impact of a number of common genetic variants on each of plasma triglycerides and HDL cholesterol.Interactions between genetic risk factors and clinical phenotypes may account for some of the unexplained heritability of plasma lipid traits. Recent studies provide biological insight into specific genetic associations and may aid in the identification of dyslipidemic patients for whom specific lifestyle interventions are likely to be most effective.