There is conclusive evidence to demonstrate the role of omega-3 polyunsaturated fatty acids (n-3 PUFA) in human development and growth, vision, and cell membrane fluidity (membrane order). N-3 PUFA also contribute to human health maintenance through correction of arrhythmias, inhibition of platelet aggregation and prolongation of clotting time, lowering blood pressure, lowering serum triglycerides and plasma homocysteine, being antiinflammatory and immunomodulatory, being cardio-protective, increasing insulin sensitivity in Asians, and decreasing the risk of breast and colorectal cancers. This understanding of a wide spectrum of biological effects attributable to n-3 PUFA has been unsettled by a systematic review of randomized clinical intervention trials (RCTs) which has reported that n-3 PUFA have negligible or no effect on all-cause or cardiovascular mortality. Here, possible reasons for the inconsistencies in regard to n-3 PUFA and cardiovascular diseases, along with the implications for their broader biology, are considered.