Cardiovascular diseases (CVD) result from complex interactions between genetic and environmental factors. The evidence supports 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 promising. Several loci (eg, APOA1, APOE, LIPC) are providing proof of concept for the application of genetics in the context of personalized nutrition for CVD prevention. The spectrum of candidate genes has been expanding to incorporate those involved in intracellular lipid metabolism (eg, iPPARs, CYP7A1). However, the practical application of these findings 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 (ie, one single dietary component, SNP, and risk factor) to more realistic situations involving multiple interactions. In summary, there is need for both large population studies and well-standardized intervention studies.