Macrophages are critical for the normal function of the innate and adaptive immune responses during host defense and are implicated in the abnormal function of these same systems when they drive inflammatory disease.1 Likely by design, lung macrophages reside at the interface of host and environment and stand ready to eradicate pathogens, noxious particles, and debris from necrotic and apoptotic cells. To accomplish their task, macrophages must be activated through ligand engagement of specific cell surface receptors. In particular, exposure to interferon-γ (IFN-γ) stimulates a classic pathway for activation that yields M1 macrophages with efficient capacities for phagocytosis and antigen presentation as well as production of T helper (Th) 1 cytokines, including IL-1β, IL-6, IL-12, and tumor necrosis factor-α, that are all important for clearance of intracellular and bacterial pathogens. By contrast, a different type of activation occurs when macrophages encounter IL-4 and IL-13, two hallmark Th2 cytokines that are implicated in the development of chronic airway disease. This second pathway antagonizes the IFN-γ-induced events of the M1 pathway and instead drives the development of alternatively activated macrophages (AAMs) that are characterized by the expression of distinct surface receptors (eg, mannose receptor), biosynthetic enzymes (eg, arachidonate 12,15 lipoxygenases), and other proteins (eg, chitinases and chitinase-like proteins and matrix metalloproteinase [MMP]-12) that are not found in M1 macrophages.2 In some definitions, AAMs include only so-called M2 macrophages that differentiate in response to IL-4 and IL-13. In other broader definitions, the term AAM refers to all macrophage subtypes that respond to any stimulus other than IFN-γ, including engagement of Fc receptors or activation with glucocorticoids, IL-10, transforming growth factor-β, or macrophage colony-stimulating factor.3 M2 macrophages are often considered to assume antiinflammatory functions, but there is compelling evidence that these cells are also important in the eradication of extracellular parasites and the pathogenesis of inflammatory airway disease. In this review, we summarize the current understanding of the biology of AAMs in mouse models of airways disease and how these findings translate to COPD, asthma, and other chronic inflammatory lung diseases in humans.