The integrated inflammatory response of the host is essential in health and disease. Hence, it is important to achieve a more complete understanding of the local cellular and molecular events that govern the formation and actions of local mediators that can serve as endogenous local mediators of resolution. Because these compounds in experimental animal models of inflammation can control the duration and magnitude of inflammation, knowledge of their formation and actions may provide new avenues for appreciating the molecular basis of many inflammatory diseases. The first of these endogenous local counterregulators recognized were the lipoxins, which are trihydroxytetraene-containing mediators generated from arachidonic acid during cell-cell interactions via transcellular biosynthesis. Because this circuit of lipoxin formation appears to be of physiological relevance in resolution, therapeutic modalities targeting this and related systems should allow for the development of novel therapeutic agents (i.e., agonists of the important cellular and physiological responses required for timely resolution). This review offers a general overview of recent advances from studies by the author and colleagues on the biosynthesis and bioactions of the novel anti-inflammatory lipid mediators, resolvins, docosatrienes, and neuroprotectins as well as their endogenous aspirin-triggered epimeric counterparts. These previously unappreciated families of lipid-derived mediators were originally isolated from experimental murine models of acute inflammation captured during the natural spontaneous resolution phase. They possess anti-inflammatory, pro-resolving, and protective properties. Inappropriate resolution mechanism(s) may underlie our current appreciation of the inflammatory phenotype(s) that characterizes many prevalent human diseases where inflammation is now acknowledged to play an important role in the disease process. Moreover, these new pathways give opportunities to appreciate the complex roles of neutrophils in the generation of potent host protective lipid mediators that may be harnessed for the design of novel treatments for a wide range of diseases where inflammation contributes to the pathophysiology of the disorder.