During the past three or four decades, there has been vast information on the effect of omega-3 on the immune system in health and in diseases, especially those caused by excessive inflammatory response. In this chapter, attempts have been made to elucidate the effect of omega-3 (n-3) on different components of the immune system, especially during child development and in aged individuals. Omega-3 is also known to reduce the pathological manifestations, especially in diseases related to inflammation, allergy and autoimmunity, which are the major challenges today. Earlier studies on the effect of polyunsaturated fatty acids on the immune system were conducted using animal systems; in this chapter, more emphasis is given to human studies. n-3 polyunsaturated fatty acids (PUFAs) have been shown to be very effective in controlling inflammation by affecting extravasation, phagocytic response and the generation of cytokines, inflammatory mediators and adhesion molecules. They also manipulate the functions of antigen-presenting cells and lymphocytes including T and B cells, natural killer (NK) cells, lymphokine-activated killer (LAK) cells and also T regulatory cells. Most of the reports on the effects of dietary omega-3 in human health have been conducted as clinical trials, extrapolated from experiences in animals and also using in vitro techniques, which have limitations. The chapter reports trials conducted to assess the effectiveness of omega-3 diet supplementation in healthy volunteers using in vitro and in vivo assays. It also deals with the effects of omega-3 diet supplementation on pregnancy and lactation, especially in relation to infant allergies. Cognizance has also been taken of the effects of omega-3 diet supplementation in the aged population. Finally, the chapter reviews important literature on the effectiveness of n-3 PUFAs in controlling inflammatory and autoimmune diseases such as rheumatoid arthritis (RA), asthma, inflammatory bowel disease (IBD), psoriasis, cardiovascular disease (CVD), diabetes, multiple sclerosis (MS) and systemic lupus erythematosus (SLE).