Inflammation is a critical aspect of the innate immune system that can determine the outcome of several economically important diseases of dairy cattle including mastitis. The purpose of the inflammatory response is to eliminate the source of tissue injury and then return tissues to normal function. Aggressive inflammatory responses, however, can cause damage to host tissues and contribute significantly to the pathophysiology of mastitis. A precarious balance between pro-inflammatory and pro-resolving mechanisms is needed to ensure optimal pathogen clearance and the prompt return to immune homeostasis. Therefore, inflammatory responses must be tightly regulated to avoid bystander damage to the milk synthesizing tissues of the mammary gland. Oxylipids are potent lipid mediators that can regulate all aspects of the inflammatory response. The biosynthetic profiles of oxylipids are dependent on both the availability of diverse polyunsaturated fatty acids substrates and their subsequent metabolism through various oxidizing pathways. Changes in lipid metabolism in dairy cows around parturition due to negative energy balance can profoundly change the composition and concentration of oxylipids in the mammary gland that may be responsible for dysfunctional inflammatory responses during this time. This presentation will provide a brief overview of the role that oxylipids play in contributing to the onset and resolution of inflammation. Factors associated with periparturient cows that can contribute to dysfunctional regulation of inflammation as a function of altered oxylipid biosynthesis and metabolism also will be described. Understanding the role oxylipids may play in mediating the onset and resolution of mastitis is key to developing novel prevention and control programs for the dairy industry.