Recent epidemiological studies highlight the key role of the type of consumed unsaturated fatty acid and the development of ulcerative colitis (UC). We aimed to review the potential mechanisms behind the antiinflammatory effects of unsaturated fatty acids on intestinal inflammation, to discuss their potential limitations, and to propose a new reappraisal of polyunsaturated fatty acids (PUFAs) in the pathophysiology of inflammatory bowel disease (IBD). A literature search using PubMed was carried out to identify relevant studies (basic science, epidemiological studies, or clinical trials) with unsaturated fatty acids and IBD. Only articles published in English were included. IBD patients exhibit an altered lipid metabolism. While in vitro and in vivo studies have demonstrated the antiinflammatory properties of n-3 polyunsaturated fatty acids in experimental models IBD, results of clinical trials have been disappointing. In addition, the impact of fatty acid on innate immunity as an alternative therapeutic approach is explored. This may offer insight into therapeutic avenues for designing n-3 PUFA diet therapy for IBD.