Dietary n-3 fatty acids and calorie restriction are well known immunomodulatory nutrients. Recent data from our laboratory has shown that combining n-3 fatty acids and calorie restriction is more potent at delaying autoimmune disease in mice than either dietary regimen alone. Interestingly, autoimmune disease has some unique effects on lymphocyte subsets and Th-1 (interleukin- 2, interferon-γ ) and Th-2 (interleukin-10 and -5) cytokine and immunoglobulin (IgA and IgE) production when comparing the peripheral blood with the spleen, mesenteric lymph nodes and salivary glands. However, regardless of the variable changes that occur due to n-6 and n-3 fatty acids, the combination of dietary n-3 fatty acids and/or calorie restriction prevents immune cell dysregulation. Extensive studies conducted in spleen T-cells have shown that diet, in the absence of pharmacologic or genetic manipulation, has a dramatic impact on preventing alterations in apoptosis, memory cell populations, and nuclear factor kappa B activation associated with autoimmune disease. The results discussed here also show striking similarities to aging in healthy mice like reduced interleukin-2 production and increased memory T-lymphocytes suggesting a clear link between normal aging and the early development of autoimmune disease. Future dietary studies examining several different immune compartments simultaneously are likely to yield exciting new data on the impact of diet and drug therapy on autoimmune disorders in various target tissues such as kidney and salivary glands.