Increased muscle oxidative stress and inflammatory responses among athletes have been reported consistently. In addition, it is well known that exhaustive or unaccustomed exercise can lead to muscle fatigue, delayed-onset muscle soreness, and a decrement in performance. Omega-3 polyunsaturated fatty acids (PUFAs) have been shown to decrease the production of inflammatory eicosanoids, cytokines, and reactive oxygen species; have immunomodulatory effects; and attenuate inflammatory diseases. While a number of studies have assessed the efficacy of omega-3 PUFA supplementation on red blood cell deformability, muscle damage, inflammation, and metabolism during exercise, only a few have evaluated the impact of omega-3 PUFA supplementation on exercise performance. It has been suggested that the ingestion of EPA and DHA of approximately 1-2 g/d, at a ratio of EPA to DHA of 2:1, may be beneficial in counteracting exercise-induced inflammation and for the overall athlete health. However, the human data are inconclusive as to whether omega-3 PUFA supplementation at this dosage is effective in attenuating the inflammatory and immunomodulatory response to exercise and improving exercise performance. Thus, attempts should be made to establish an optimal omega-3 fatty-acid dosage to maximize the risk-to-reward ratio of supplementation. It should be noted that high omega-3 PUFA consumption may lead to immunosuppression and prolong bleeding time. Future studies investigating the efficacy of omega-3 PUFA supplementation in exercise-trained individuals should consider using an exercise protocol of sufficient duration and intensity to produce a more robust oxidative and inflammatory response.