In simple terms, inflammation can be defined as a beneficial, nonspecific response of tissues to injury that generally leads to restoration of normal structure and function. In this concept, resolution of the inflammatory response, once it has achieved its protective and pro-immunogenic functions, becomes a critical determinant of what might be considered the paradox of inflammation. On one hand, inflammation is essential to resolve tissue injury and maintain homeostasis. On the other, inflammation is a key participant in the great majority of human diseases. Accordingly, to achieve complete resolution of inflammation, it is necessary to both turn off inflammatory mediator production and inflammatory cell accumulation and to remove inflammatory cells and debris without initiating an autoimmune response. Much of this process involves key activities of the mononuclear phagocyte series of cells, including resident and recruited macrophages. Recognition of activated and dying acute inflammatory cells by mononuclear phagocytes has been shown to (a) enhance macropinocytic activity for removal of debris, (b) enhance uptake of the effete inflammatory cells themselves, (c) induce inflammosuppressive and immunosuppressive mediators such as TGFβ and IL-10 that can down-regulate and limit proinflammatory mediator production, and (d) induce production of growth factors for tissue cells that may play key roles in tissue repair. Defects in these highly regulated processes are associated with persistent inflammation and/or autoimmunity in overaggressive resolution mechanisms such as nonresolving fibrosis or persistent tissue destruction as in emphysema.