Evidence-based systematic reviews evaluating dietary intake and nutritional interventions are becoming common but are relatively few compared with other applications. Concerns remain that systematic reviews of nutrition topics pose several unique challenges. We present a successful collaboration to systematically review the health effects of a common nutrient, n-3 (or omega-3) fatty acids, across a wide range of clinical conditions. More generally, we discuss the challenges faced and the lessons learned during the review, the benefits of systematic review of nutritional topics, and recommendations for conducting and reviewing nutrition-related studies. Through a structured but flexible process, 3 Evidence-based Practice Centers in the Agency for Healthcare Research and Quality program produced 11 reports on a wide range of n-3 fatty acid-related topics. An important resource has been created, through which nutrition and dietetics researchers, clinical dietitians and nutritionists, clinicians, and the general public can understand the state of the science. The process identified challenges and problems in evaluating the health effects of n-3 fatty acid consumption, highlighted challenges to reviewing the human nutrition literature, and yielded recommendations for future research. The goals of these systematic reviews, the processes that were used, the benefits and limitations of the collaboration, and the conclusions of the reviews, including recommendations for future research, are summarized here.