Cardiovascular disease (CVD) results from complex interactions between genetic and environmental factors. The evidence supports that gene–environment interactions modulate plasma lipid concentrations and potentially CVD risk. Several genes (eg, apolipoprotein A-I and A-IV, apolipoprotein E, and hepatic lipase) 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 and especially those transcription factors (ie, peroxisome proliferator activator receptors) that act as sensors of nutrients in the cell (eg, polyunsaturated fatty acids) to trigger metabolic responses through activation of specific sets of genes. However, current knowledge is still very limited and so is the potential benefit of its application to clinical practice. Thinking needs to evolve from simple scenarios (eg, one single dietary component, a single nucleotide polymorphism and risk factor) to more realistic situations involving multiple interactions. One of the first situations where personalized nutrition is likely to be beneficial is in patients with dyslipidemia who require special intervention with dietary treatment. This process could be more efficient if the recommendations were carried out based on genetic and molecular knowledge. Moreover, adherence to dietary advice may increase when it is supported with information based on nutritional genomics, and a patient believes the advice is personalized. However, a number of important changes in the provision of health care are needed to achieve the potential benefits associated with this concept, including a teamwork approach with greater integration among physicians, food and nutrition professionals, and genetic counselors.