Cardiovascular disease (CVD) risk is the result of complex interactions between genetic and environmental factors. During the past few decades, much attention has focused on plasma lipoproteins as CVD risk factors. The current evidence supports the concept that gene-environment interactions modulate plasma lipid concentrations and potentially CVD risk. The findings from studies examining gene-diet interactions and lipid metabolism have been highly promising. Several loci (i.e., APOA1, APOA4, APOE, and LIPC) are providing proof-of-concept for the potential application of genetics in the context of personalized nutritional recommendations for CVD prevention. However, the incorporation of these findings to the clinical environment is not ready for prime time. There is a compelling need for replication using a higher level of scientific evidence. Moreover, we need to evolve from the simple scenarios examined nowadays (i.e., one single dietary component, single nucleotide polymorphism, and risk factor) to more realistic situations involving interactions between multiple genes, dietary components, and risk factors. In summary, there is need for both large population studies and well-standardized intervention studies.