Resolution of inflammation has historically been viewed as a passive process, occurring as a result of the withdrawal of pro-inflammatory signals, including lipid mediators such as leukotrienes and prostaglandins. Thus, most anti-inflammatory drugs have traditionally targeted primarily mediator pathways that are engaged at the onset of inflammation. Only recently has it been established that inflammation resolution is an active process with a distinct set of chemical mediators. Several clinical and epidemiological studies have identified beneficial effects of polyunsaturated fatty acids (PUFAs) for a variety of inflammatory diseases, yet without mechanistic explanations for these beneficial effects. Resolvins and protectins are recently identified molecules that are generated from omega-3 PUFA precursors and can orchestrate the timely resolution of inflammation in model systems. Dysregulation of pro-resolving mediators is associated with diseases of prolonged inflammation, so designing pharmacological mimetics of naturally occurring pro-resolving mediators offers exciting new targets for drug design. This review describes the discovery and synthesis of these novel lipid mediators, their receptors and mechanisms of action, and summarizes the studies to date that have uncovered roles for resolvins and protectins in disease states.