Dietary intake of fish and ω–3 polyunsaturated fatty acids (ω–3 PUFAs) may decrease the risk of prostate cancer development and progression to advanced stage disease. This could reflect the anti-inflammatory effects of PUFAs, possibly through mediation of cyclooxygenase (COX), a key enzyme in fatty acid metabolism and inflammation. Despite promising experimental evidence, epidemiological studies have reported somewhat conflicting results regarding the effects of fish/PUFAs on prostate cancer development and progression. The literature suggests that fish, and particularly long-chain ω–3 PUFAs, may have a more pronounced protective effect on biologically aggressive tumors or on their progression, and less on early steps of carcinogenesis. Moreover, the impact of LC ω–3 PUFAs may be modified by variation of the COX-2 gene. Overall, results to date support the hypothesis that long-chain ω–3 PUFAs may impact prostate inflammation and carcinogenesis via the COX-2 enzymatic pathway.