Plasma lipids are important risk factors for cardiovascular disease. Both genetic factors and diet are known to regulate lipid levels, and there has been a longstanding interest in how genes may interact with diet to modulate changes in lipid levels. Genome-wide association studies have recently identified the genes most strongly associated with variation in lipids within a population. In this paper, the current knowledge on gene–diet interactions to regulate lipid levels is discussed in light of these studies. Future genome-wide studies are required that specifically identify genes that are important modulators of lipid levels in response to dietary change. Some methodologic challenges inherent in these studies are discussed.