This review examines issues related to the development of a recommended daily allowance or adequate intake, two of the categories of dietary reference intakes, for the long-chain omega-3 polyunsaturated fatty acids (omega-3 PUFAs), eicosapentaenoic acid (EPA, 20:5 n-3), and docosahexaenoic acid (DHA, 22:6 n-3). Although some have suggested a dietary intake of two servings of fatty fish per week or supplement intake of 500 mg/day EPA plus DHA, based on evidence from epidemiologic and clinical studies of cardiovascular benefit from regular fish or fish-oil consumption, supplementation with EPA and/or DHA may also have antidepressant and mood-stabilizing effects. Omega-3 PUFA biology is complex and chronic disease outcomes are sometimes difficult to prove, yet the possibility of benefit for a substantial portion of the population from increased omega-3 PUFA intake is a public health issue that must be addressed responsibly and be based on significant scientific evidence.