Omega-3 (-3) polyunsaturated fatty acids (PUFA) and their metabolites have long been recognized to protect against inflammation-related diseases including heart disease. Recent reports present conflicting evidence on the effects of -3 PUFAs on major cardiovascular events including death. While some studies document that -3 PUFA supplementation reduces the risk for heart disease, others report no beneficial effects on heart disease composite primary outcomes. Much of this heterogeneity may be related to the genetic variation in different individuals/populations that alters their capacity to synthesize biologically active -3 and omega 6 (-6) PUFAs and metabolites from their 18 carbon dietary precursors, linoleic acid (LA, 18:2 -6) and alpha-linolenic (ALA, 18:3, -3). Here, we discuss the role of a gene-by-dietary PUFA interaction model that takes into consideration dietary exposure, including the intake of LA and ALA, -3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in determining the efficacy of -3 PUFA supplementation. We also review recent clinical trials with -3 PUFA supplementation and coronary heart disease in the context of what is known about fatty acid desaturase ( gene-by-dietary PUFA interactions. Given the dramatic differences in the frequencies of variants that impact the efficiency of -3 and -6 PUFA biosynthesis, and their downstream signaling products among global and admixture populations, we conclude that large clinical trials utilizing "one size fits all" -3 PUFA supplementation approaches are unlikely to show effectiveness. However, evidence discussed in this review suggests that -3 PUFA supplementation may represent an important opportunity where precision interventions can be focused on those populations that will benefit the most from -3 PUFA supplementation.