It has long been known that there is an extremely high degree of variability in both human and nonhuman primates in terms of low density lipoprotein cholesterol (LDL-C) lowering in response to restriction of dietary saturated fat and cholesterol. In this regard we have reviewed the current knowledge regarding the gene-diet interaction in relation to plasma lipid response to dietary intervention. Several candidate gene loci have been examined in humans: apolipoprotein (apo) A-I, apo A-IV, apo B, apo C-III and apo E, as well as lipoprotein lipase (LPL). Several mutations at these loci have been found to be associated with responsiveness. We and others have documented that subjects carrying the apo E4 allele are more responsive with regard to LDL-C lowering in response to dietary fat and cholesterol restriction than subjects carrying the apo E3 or apo E2 alleles, whereas some studies report no association of apo E phenotypes with lipid response to some dietary interventions. Our own meta-analysis indicates that apo E genotype effects are modulated via alterations of amount and type of dietary fat. We have also documented that subjects carrying the common glutamine for histidine mutation at amino acid 360 of apo A-IV are significantly less responsive in terms of LDL-C lowering than subjects with the normal apo A-IV genotype is modulated via changes in dietary cholesterol. In addition, we have documented that the common G/A mutation within the promoter region of the apo A-I gene is associated with greater responsiveness of LDL-C to dietary fat alterations. The XbaI and insertion/deletion polymorphisms at the apo B gene locus and the HindIII restriction fragment length polymorphism (RFLP) at the LPL locus have also been associated with diet responsiveness. Therefore, in humans these gene loci account for a significant portion of the variability in plasma lipid response to dietary alterations.