Resolution of acute lung inflammation and injury is an active process, not merely the absence of pro-inflammatory signals. Restoration of homeostasis is coordinated by specific mediators and cellular events. In response to injury and inflammatory stimuli, infiltrating leukocytes and tissue-resident cells interact to generate lipoxins (LXs), bioactive eicosanoids derived from arachidonic acid. In contrast to pro-inflammatory leukotrienes and prostaglandins, LXs display potent anti-inflammatory actions. LXA₄ interacts with a G protein-coupled receptor termed ALX that transduces counter-regulatory signals, in part via intracellular polyisoprenyl phosphate remodeling. Presqualene diphosphate (PSDP) is a polyisoprenyl phosphate in human neutrophils that is rapidly converted to presqualene monophosphate (PSMP) upon cell activation. PSDP, but not PSMP directly inhibits phospholipase D, phosphoinositol-3 kinase and superoxide anion generation. LXs block PSDP turnover in PMN membranes to prevent pro-inflammatory responses. Hence, LX and polyisoprenyl phosphate signaling provide a counter-regulatory circuit to promote resolution of acute lung inflammation. LXA₄ and PSDP mimetics have been prepared with potent protective actions in murine models of asthma and acute lung injury.