Many human diseases have been linked to inflammation, which is mediated by a number of chemical molecules including lipid mediators and cytokines. Polyunsaturated fatty acids (omega-6 and omega-3 fatty acids) are the precursors of the lipid mediators and play an important role in regulation of inflammation. Generally, omega-6 fatty acids (e.g. arachidonic acid) promote inflammation whereas omega-3 fatty acids (e.g. eicosapentaenoic acid and docosahexaenoic acid) have anti-inflammatory properties. Omega-3 fatty acids dampen inflammation through multiple pathways. On the one hand, omega-3 fatty acids inhibit the formation of omega-6 fatty acids-derived pro-inflammatory eicosanoids (e.g. PGE2 and LTB4), and on the other hand these fatty acids can form several potent anti-inflammatory lipid mediators (e.g. resolvins and protectins). These together directly or indirectly suppress the activity of nuclear transcription factors, such as NFkappaB, and reduce the production of pro-inflammatory enzymes and cytokines, including COX-2, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta. This chapter focuses on the evidence from recent studies using new experimental models.