Fish oil supplementation is commonplace in human nutrition and is being used in both enteral and parenteral formulations during the treatment of patients with a large variety of diseases and immune status. The biological effects of fish oil are believed to result from their content of -3 polyunsaturated fatty acids (PUFA), particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). These fatty acids are known to have numerous effects upon immune functions and are described as immunomodulatory. However, immunomodulatory is a nondescript term that encompasses immunostimulation and immunosuppression. The primary goal of this review is to better describe the immune effects of -3 PUFA as they relate to immunostimulatory vs. immunosuppressive effects. One mechanism proposed for the immune effects of -3 PUFA relates to the production of specialized pro-resolving mediators (SPMs). A second goal of this review is to evaluate the effects of -3 PUFA supplementation upon production of SPMs. Although -3 PUFA are stated to possess anti-oxidative properties, these molecules are highly oxidizable due to multiple double bonds and may increase oxidative stress. Thus, the third goal of this review is to evaluate the effects of -3 PUFA upon lipid oxidation. We conclude, based upon current scientific evidence, that -3 PUFA suppress inflammatory responses and most cellular immune responses such as chemotaxis, transmigration, antigen presentation, and lymphocyte functions and should be considered immunosuppressive. -3 PUFA induced production of resolution molecules is inconsistent with many resolution molecules failing to respond to -3 PUFA supplementation. -3 PUFA supplementation is associated with increased lipid peroxidation in most studies. Vitamin E co-administration is unreliable for prevention of the lipid peroxidation. These effects should be considered when administering -3 PUFA to patients that may be immunosuppressed or under high oxidative stress due to illness or other treatments.