The cellular events underlying the resolution of acute inflammation are not known in molecular terms. To identify anti-inflammatory and proresolving circuits, we investigated the temporal and differential changes in self-resolving murine exudates using mass spectrometry-based proteomics and lipidomics. Key resolution components were defined as resolution indices including Ψ max, the maximal neutrophil numbers that are present during the inflammatory response; T max, the time when Ψ max occurs; and the resolution interval (R i) from T max to T 50 when neutrophil numbers reach half Ψ max. The onset of resolution was at∼ 12 h with proteomic analysis showing both haptoglobin and S100A9 levels were maximal and other exudate proteins were dynamically regulated. Eicosanoids and polyunsaturated fatty acids first appeared within 4 h. Interestingly, the docosahexaenoic acid-derived anti-inflammatory lipid mediator 10, 17S-docosatriene was generated during the R i. Administration of aspirin-triggered lipoxin A 4 analog, resolvin E1, or 10, 17S-docosatriene each either activated and/or accelerated resolution. For example, aspirin-triggered lipoxin A 4 analog reduced Ψ max, resolvin E1 decreased both Ψ max and T max, whereas 10, 17S-docosatriene reduced Ψ max, T max, and shortened R i. Also, aspirin-triggered lipoxin A 4 analog markedly inhibited proinflammatory cytokines and chemokines at 4 h (20–50% inhibition), whereas resolvin E1 and 10, 17S-docosatriene’s inhibitory actions were maximal at 12 h (30–80% inhibition). Moreover, aspirin-triggered lipoxin A 4 analog evoked release of the antiphlogistic cytokine TGF-β. These results characterize the first molecular resolution circuits and their major components activated by specific novel lipid mediators (ie, resolvin E1 and 10, 17S-docosatriene) to promote resolution.