Socioeconomic development has resulted in an epidemiologic transition which has involved an increase in mortality and morbidity from chronic non-communicable diseases. Cardiovascular disease is one such disease. The rapidity with which this transition has occurred suggests that genetic factors are unlikely to be responsible. However, studies in twins suggest significant heritability for cardiovascular disease and its associated risk factors. We present data showing diet-gene interactions involving polymorphisms at the PPARA and PLIN loci. These data support the hypothesis that chronic diseases such as cardiovascular disease are a consequence of a complex interplay of genetic and environmental factors, of which diet plays an important role. They suggest that the effects of diet on chronic disease may be masked by heterogeneity of effect related to genetic variability between individuals and that consideration of diet-gene interactions may contribute to our understanding of the pathogenesis of cardiovascular disease. The identification of diet-gene interactions offers us an opportunity to develop dietary interventions that will obviate the effects of genetic factors on the risk of disease. In this way, we may be able to develop personalized dietary recommendations that optimize the outcome for the individual concerned. Nevertheless, while existing data points to the value of these studies, significant challenges need to be met to ensure that our conclusions are scientifically valid.