The mononuclear phagocyte system is the central body defense called upon to deal with persistent foreign objects or irritants. Depending on circumstances, the macrophages function as phagocytes or secretory cells or both. Granulomas may form in the absence of immunologic modulation (foreign body granuloma) or they may develop under immunologic control (hypersensitivity granulomas). In either case, the secretory products of macrophages are qualitatively similar and differ mainly in the total amounts produced. If cell-mediated immunity dictates hypersensitivity granulomas as commonly taught, one has to explain what aberrent signals are sent from T cells or what abnormal message is perceived in the macrophages which causes them to differentiate to purely secretory epithelioid cells or produce such abnormal pathologic patterns as necrobiosis. Alternatively, some granulomatous hypersensitivity reactions such as organized epithelioid cell granulomas may be initiated primarily by a macrophage secretion product with cellular immunity acting to amplify or promote granuloma formation and organization. The known heterogeneity of macrophages is insufficient to account for the varied observations. Future experimentation will uncover the different differentiation programs of monocytes required for the varied and various granulomas seen in skin.