Cardiovascular disease is an inflammatory process and the leading cause of death in the United States. Novel omega-3 derived potent lipid mediators, termed resolvins and protectins, have been identified as major pathophysiologic players in the resolution phase of the inflammatory response. Potent lipid mediators offer tremendous metabolic and pathophysiologic insights in regard to the risk and treatment of cardiovascular disease. In this review, resolvins and protectins are described and analyzed as accelerators of discovery via their potential role as biomarkers for research and clinical decision making in cardiovascular disease. Specific barriers relating to biomarker validation, laboratory methods, and improvement of risk models are introduced and discussed.